Efficient synthesis of novel 1-hydroxy-2,4,5-trisubstituted imidazole derivatives via a one-pot, four-component reaction between hydroxylamine, benzonitriles, arylglyoxals and cyclic 1,3-dicarbonyl compounds

Article abstract of DOI:10.24820/ark.5550190.p010.984

A simple, and efficient procedure for the synthesis of novel 2,5-diaryl-1-hydroxy-1H-imidazol-4-yl derivatives via a one-pot, four-component reaction between hydroxylamine, benzonitriles, arylglyoxals and cyclic 1,3-dicarbonyl compounds (Melrum’s acid or dimedone) in ethanol under reflux conditions without using bases and catalysts is reported. All the products were obtained in good yields and their structures were established from their spectroscopic data.

Full text of DOI:10.24820/ark.5550190.p010.984

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Organic Chemistry
Arkivoc 2019, part vi, 0-0
Efficient synthesis of novel 1-hydroxy-2,4,5-trisubstituted imidazole derivatives
via a one-pot, four-component reaction between hydroxylamine, benzonitriles,
arylglyoxals and cyclic 1,3-dicarbonyl compounds
Farzaneh Alizadeh-Bami, Mina Salehzadeh, Hossein Mehrabi,* and Reza Ranjbar-Karimi
Department of Chemistry, Vali-e-Asr University of Rafsanjan, 77176 Rafsanjan, Iran
E-mail: mehraby_h@yahoo.com
Received 05-25-2019
Accepted 07-22-2019
Published on line 08-04-2019
Abstract
A simple, and efficient procedure for the synthesis of novel 2,5-diaryl-1-hydroxy-1H-imidazol-4-yl derivatives
via a one-pot, four-component reaction between hydroxylamine, benzonitriles, arylglyoxals and cyclic 1,3-
dicarbonyl compounds (Melrum’s acid or dimedone) in ethanol under reflux conditions without using bases
and catalysts is reported. All the products were obtained in good yields and their structures were established
from their spectroscopic data.
Keywords: 1-Hydroxy-2,4,5-trisubstituted imidazoles, hydroxylamine, benzonitriles, arylglyoxals, 1,3-
dicarbonyl compounds, dimedone, Meldrum’s acid
DOI: https://doi.org/10.24820/ark.5550190.p010.984
Page 1
©ARKAT USA, Inc

Arkivoc 2019, vi, 0-0
Alizadeh-Bami, F. et al.
Introduction
Hydroxy-imidazole derivatives have attracted great attention in recent years1 due to their exhibiting a wide
spectrum of biological activities such as the anti-HIV A,2 anti-inflammatory B,3 antibacterial C,4,5 antiprotozoal
D,6 and antihypertensive E agents (Figure 1).7
CO2Et
N
HO
NH
O
O
N
Me
Me
F
HO(H2C)2
N
N
O
O
N
O
A
B
Me
F
CONH2
NH2
Cl
Me
Me
HN
N
N
Me
N
N
N
OH
HO
O
C
D
E
Figure 1. Selected bioactive molecules containing a 1-hydroxy-imidazole moiety.
Some 1-hydroxy-imidazole derivatives, such as metronidazole,8,9 are present in drugs for treatment of
parasitic diseases and they have applications in biochemistry, dye production, corrosion science,10 and as
transition metal chelating agents.11 Also, 1-hydroxy-imidazoles may be used as insecticides or as plant growth
regulators.12,13 As a result, studies on efficient syntheses of 1-hydroxy-imidazole derivatives have received
much attention.
Over the past years, several successful methods have been reported for the preparation of 1-hydroxy
imidazoles and related compounds. The mostly used methods are as follows: (a) condensations of α-
hydroxyimino ketones with N-methyleneamines;14-16 (b) cyclocondensation of α-amino oxime derivatives with
orthoesters;17 (c) reaction of 1,2-diimines with oxime derivatives;18 (d) condensation of α-hydroxyimino
ketones with various methylidene alkylamines;19 (e) three-component reaction of α-hydroxyimino ketones
with a primary amine and aldehyde derivatives;20 (f) via directed lithiation and metal-halogen exchange;7 (g)
[3+2] cycloaddition of oximino carbenoids with nitriles;21 (h) three-component coupling between α-
hydroxyimino ketone, aldehydes and ammonium acetate;2 (i) four-component reaction of benzil, aromatic
aldehydes, an amine, and ammonium acetate;22,23 (j) condensation of benzil, an aldehyde, and ammonium
acetate in the presence of different catalysts;24,25 and (k) one-pot [2+2+1] cycloannulation of 1,3-
bishet(aryl)monothio-1,3-diketones, α-substituted methylamines and sodium nitrite.26
However, many of these methods have one or more disadvantages, such as the use of hazardous organic
solvents, long reaction times, low yields, tedious work-up procedures, and use of expensive catalysts. With this
background in mind and in continuation of our previous work on the development of multicomponent
approaches for the synthesis of new heterocycles,27,28 we describe a new strategy for the synthesis of 1-
hydroxy-2,4,5-trisubstituted imidazoles by a one-pot, four-component reaction of a hydroxylamine, a
benzonitriles, a cyclic 1,3-dicarbonyl compound, and an arylglyoxal.
Page 2
©ARKAT USA, Inc

Arkivoc 2019, vi, 0-0
Alizadeh-Bami, F. et al.
Results and Discussion
To find the optimized conditions, we studied the synthesis of 5-(5-(4-chlorophenyl)-1-hydroxy-2-phenyl-1H-
imidazol-4-yl)-6-hydroxy-2,2-dimethyl-4H-1,3-dioxin-4-one 5a via the four-component reaction of
hydroxylamine 1, benzonitrile 2a, Meldrum's acid 3, and 4-chlorophenylglyoxal 4a, with a 2.0:1.0:1.0:1.0 molar
ratio, under a variety of conditions (Table 1).
Table 1. Optimization of the reaction conditions
Entry
1
2
3
4
5
6
7
8
Solvent
H2O
CH3CN
DMF
Temp.(oC)a
r.t.
Yield (%)b
Trace
Trace
Trace
Trace
Trace
Trace
10
r.t.
r.t.
r.t.
r.t.
THF
MeOH
EtOH
H2O
CH3CN
DMF
r.t.
reflux
reflux
reflux
reflux
reflux
reflux
refluxc
13
30
15
25
82
82
9
10
11
12
13
THF
MeOH
EtOH
EtOH
a Reaction conditions: 1 (2.0 mmol), 2a (1.0 mmol), 3 (1.0 mmol),
4a (1.0 mmol), solvent volume 10.0 mL and reaction time was 4 h.
b Isolated yields.
c Reaction time was 24 h.
When the reaction was carried out in a variety of solvents: water, acetonitrile, N,N-dimethylformamide
(DMF), tetrahydrofuran (THF), methanol, and ethanol (Table 1, entries 1-6) at room temperature, only a trace
of product was obtained but when the reaction was carried out in water, acetonitrile, DMF, THF, methanol,
and ethanol at reflux, the product was obtained in yields of 10%, 13%, 30%, 15%, 25%, and 82% respectively
(Table 1, entries 7-12). Extending the reaction time in refluxing ethanol did not improve the yield (Table 1,
entry 13). Having optimized conditions in hand, we now explored the scope of this novel transformation for
various substituted benzonitriles 2, and arylglyoxals 4 and the results are summarized in Table 2.
Page 3
©ARKAT USA, Inc

Arkivoc 2019, vi, 0-0
Alizadeh-Bami, F. et al.
As can be seen from Table 2, the nature of the benzonitriles and the arylglyoxal were important. When the
benzonitrile, and especially the arylglyoxal, carried electron-withdrawing groups (for example, halide and
nitro), higher yields were achieved.
Table 2. Synthesis of 1-hydroxy-2,4,5-trisubstituted imidazole derivatives
Product
R
1,3-Dicarbonyl
compound
Ar
Yield(%) a,b
5a
5b
5c
5d
5e
5f
C6H5
CH2C6H5
2-ClC6H4
4-OCH3C6H4
C6H5
4-ClC6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-ClC6H4
C6H5
82
65
85
72
76
78
70
68
82
72
75
87
C6H5
5g
5h
5i
C6H5
C6H5
4-CH3C6H4
4-ClC6H4
4-CH3C6H4
C6H5
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
5j
5k
5l
4-NO2C6H4
a Isolated yields.
b Reaction time was 4 h.
Page 4
©ARKAT USA, Inc

Arkivoc 2019, vi, 0-0
Alizadeh-Bami, F. et al.
1
All the synthesized compounds were unknown and were characterized by H and 13C NMR, IR, CHN analysis
1
and melting points. For instance, the H NMR spectrum of the compound 5a consisted of a singlet at δ 1.64
ppm for the methyl groups in the Meldrum's acid unit and a singlet that integrated for one hydrogen was
observed at δ 2.06 ppm for the hydroxy proton. The aromatic protons resonated in the region δ 7.51–8.04
ppm and a broad singlet that integrated for one hydrogen was observed at δ 14.10 ppm for the hydroxy
proton. The 13C NMR spectrum of compound 5a exhibited 16 distinct signals in agreement with the proposed
structure. In the IR spectrum, the hydroxyl and the carbonyl lactone absorption were observed at 3424 and
1639 cm−1. Partial assignments of these resonances for the other products are given in the Experimental
Section.
The possible mechanism for the synthesis of 1-hydroxy-2,4,5-trisubstituted imidazole derivatives 5 is
illustrated in Scheme 1. Firstly, intermediate A is formed by the addition of the hydroxylamine 1 to the
benzonitrile 2. Also, intermediate B is formed by means of a Knoevenagel condensation between the
arylglyoxal 3 and 1,3-dicarbonyl compound 4, Meldrum's acid or dimedone. Then, Michael addition of
amidoxime A (as Michael donor) to α,β-unsaturated γ-dicarbonyl species B (as Michael acceptor) provides
intermediate C, which subsequently undergoes intramolecular nucleophilic addition to form intermediate D. In
the last step, 1-hydroxy-2,4,5-trisubstituted imidazole derivative 5 is formed by elimination of H2O and
intramolecular H-shift.
OH
R
CN
2
O
H2N
NH
O
1
O
EtOH
reflux
+
OH
R
N
H
+
Ar
H
A
B
Ar
O
O
O
O
Michael
addition
3
4
Ar
O
O
O
Ar
O
OH
HO
R
O
HO
H-Shift
N
N
Ar
N
-H2O
N
N
R
NH
O
H O
HO
D
5
C
R
Scheme 1. Proposed mechanism of the reaction.
Conclusions
We have successfully developed a novel and four-component reaction for synthesis of 1-hydroxy-2,4,5-
trisubstituted imidazoles via hydroxylamine, benzonitriles, arylglyoxal and Meldrum’s acid or dimedone in
ethanol under reflux conditions. This efficient strategy has the advantages of catalyst-free, easy work-up, high
yields, short reaction time, and an environmentally benign procedure.
Page 5
©ARKAT USA, Inc

Arkivoc 2019, vi, 0-0
Alizadeh-Bami, F. et al.
Experimental Section
General. All chemicals were purchased from Aldrich and Merck with high-grade quality, and used without any
purification. All melting points were obtained by Barnstead Electrothermal 9200 apparatus and are
uncorrected. The reactions were monitored by TLC and all yields refer to isolated products. NMR spectra were
obtained on a Varian 500 MHz spectrometer (1H NMR at 500 MHz, 13C NMR at 125 MHz) in DMSO-d6 using
TMS as an internal standard. Infrared spectra were recorded on a Bruker FT-IR Equinax-55 spectrophotometer
in KBr with absorption in cm-1. Elemental analyses were performed using a Carlo Erba EA 1108 instrument. All
products were characterized by their spectroscopic and physical data.
General procedure for the synthesis of 1-hydroxy-2,4,5-trisubstituted imidazole derivatives.
A mixture of hydroxylamine (1) (2.0 mmol) and benzonitrile (2) (1.0 mmol) was stirred in EtOH (10 mL) at
reflux for 3 h to give the amidoxime. Then, Meldrum’s acid (3) (1.0 mmol) and an arylglyoxal (4) (1.0 mmol)
were added, and the resulting mixture stirred at reflux for 1 h. After completion of the reaction, determined
by TLC analysis, the solvent was removed under reduced pressure, and the resulting crude product was
purified by recrystallization from EtOH to give the pure compounds 5a–l (65–87%).
5-(5-(4-Chlorophenyl)-1-hydroxy-2-phenyl-1H-imidazol-4-yl)-6-hydroxy-2,2-dimethyl-4H-1,3-dioxin-4-one
o
1
(5a). mp 213-215 C. IR ʋ/cm-1 (KBr): 3424, 2991, 1639. H NMR (500 MHz, DMSO-d6): δ 1.64 (s, 6H, 2CH3),
2.06 (s, 1H, OH), 7.51 (d, J 10.0 Hz, 2H, ArH), 7.55 (s, 2H, ArH), 7.56 (d, J 5.0 Hz, 2H, ArH), 7.63 (s, 1H, ArH), 8.04
(m, 2H, ArH), 14.10 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6): δ 26.2, 102.2, 122.3, 125.4, 126.5, 128.5,
129.1, 129.3, 129.8, 131.5, 131.5, 131.8, 135.9, 161.8, 165.3, 196.5 ppm. Anal. Calcd for C21H17ClN2O5 (412.83):
C, 61.10; H, 4.15; N, 6.79. Found: C, 61.24; H, 4.17; N, 6.75%.
5-(2-Benzyl-1-hydroxy-5-(p-tolyl)-1H-imidazol-4-yl)-6-hydroxy-2,2-dimethyl-4H-1,3-dioxin-4-one (5b). mp
o
208-211 C. IR ʋ/cm-1 (KBr): 3432, 2998, 1667; 1H NMR (500 MHz, DMSO-d6): δ 1.22 (s, 6H, 2CH3), 1.58 (s, 3H,
CH3), 2.07 (s, 1H, OH), 3.76 (s, 2H, CH2), 6.67 (d, J 10.0 Hz, 2H, ArH), 6.78 (d, J 10.0 Hz, 1H, ArH), 6.82 (s, 2H,
ArH), 6.84 (d, J 7.9 Hz, 2H, ArH), 6.92 (d, 2H, J 7.9 Hz, ArH), 13.31 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-
d6): δ 20.8, 25.6, 28.9, 62.6, 101.7, 123.2, 123.7, 125.8, 126.1, 127.1, 128.3, 128.5, 128.6, 133.6, 136.1, 137.6,
165.1, 191.2 ppm. Anal. Calcd for C23H22N2O5 (406.44): C, 67.97; H, 5.46; N, 6.89. Found: C, 67.19; H, 5.50; N,
6.91%.
5-(2-(2-Chlorophenyl)-5-(4-chlorophenyl)-1-hydroxy-1H-imidazol-4-yl)-6-hydroxy-2,2-dimethyl-4H-1,3-
o
1
dioxin-4-one (5c). mp 204-206 C. IR ʋ/cm-1 (KBr): 3420, 2987, 1609; H NMR (500 MHz, DMSO-d6): δ 1.05 (s,
1H, OH), 1.65 (s, 6H, 2CH3), 7.55 (d, J 5.0 Hz, 2H, ArH), 7.64 (d, J 5.0 Hz, 2H, ArH), 7.71 (t, 2H, ArH), 7.78 (d, J 6.9
Hz, 1H, ArH), 7.87 (d, J 7.7 Hz, 1H, ArH), 13.85 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6): δ 26.3, 69.2,
102.0, 111.8, 115.6, 122.4, 128.1, 128.4, 128.8, 129.0, 130.5, 133.6, 134.0, 134.7, 135.1, 144.2, 164.8, 214.0
ppm. Anal. Calcd for C21H16Cl2N2O5 (447.27): C, 56.39; H, 3.61; N, 6.26%.
5-(5-(4-Chlorophenyl)-1-hydroxy-2-(4-methoxyphenyl)-1H-imidazol-4-yl)-6-hydroxy-2,2-dimethyl-4H-1,3-
o
1
dioxin-4-one (5d). mp 203-205 C. IR ʋ/cm-1 (KBr): 3422, 2938, 1610. H NMR (500 MHz, DMSO-d6): δ 1.61 (s,
6H, 2CH3), 2.08 (s, 1H, OH), 3.86 (s, 3H, CH3), 7.20 (d, J 9.0 Hz, 2H, ArH), 7.54 (d, J 8.6 Hz, 2H, ArH), 7.69 (d, J 8.6
Hz, 2H, ArH), 8.04 (d, J 9.0 Hz, 2H, ArH), 13.51(s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6): δ 26.3, 56.0,
68.1, 101.7, 111.3, 115.0, 126.6, 128.4, 128.6, 128.8, 129.2, 130.4, 133.2, 136.9, 141.1, 164.9, 217.0 ppm. Anal.
Calcd for C22H19ClN2O6 (442.85): C, 59.67; H, 4.32; N, 6.33. Found: C, 59.79; H, 4.33; N, 6.28%.
5-(5-(4-Bromophenyl)-1-hydroxy-2-phenyl-1H-imidazol-4-yl)-6-hydroxy-2,2-dimethyl-4H-1,3-dioxin-4-one
o
1
(5e). mp 218-220 C. IR ʋ/cm-1 (KBr): 3426, 2986, 1639. H NMR (500 MHz, DMSO-d6): δ 1.63 (s, 6H, 2CH3),
Page 6
©ARKAT USA, Inc

Arkivoc 2019, vi, 0-0
Alizadeh-Bami, F. et al.
2.08 (s, 1H, OH), 7.55 (d, J 5.0 Hz, 2H, ArH), 7.64 (d, J 5.0 Hz, 2H, ArH), 7.68 (s, 1H, ArH), 7.70 (d, J 10.0 Hz, 2H,
ArH), 8.07 (d, J 10.0 Hz, 2H, ArH), 13.75 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6): δ 26.3, 78.7, 101.8,
127.4, 128.7, 128.9, 129.3, 129.5, 131.4, 131.7, 132.8, 133.9, 136.7, 140.7, 164.9, 187.4 ppm. Anal. Calcd for
C21H17BrN2O5 (457.28): C, 55.16; H, 3.75; N, 6.13. Found: C, 55.24; H, 3.77; N, 6.08%.
2-(5-(4-Chlorophenyl)-1-hydroxy-2-phenyl-1H-imidazol-4-yl)-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one
(5f). mp 205-207 oC. IR ʋ/cm-1 (KBr): 3449، 2954, 1694. 1H NMR (500 MHz, DMSO-d6): δ 1.09 (s, 6H, 2CH3), 2.59
(s, 1H, OH), 3.17 (s, 2H, CH2), 3.32 (d, 2H, CH2), 7.55 (d, J 5.0 Hz, 2H, ArH), 7.57 (s, 1H, ArH), 7.61 (d, J 10.0 Hz,
2H, ArH), 7.81 (d, J 5.0 Hz, 2H, ArH), 8.43 (d, J 10.0 Hz, 2H, ArH), 14.01 (s, 1H, OH) ppm. 13C NMR (125 MHz,
DMSO-d6): δ 28.1, 32.9, 45.7, 51.4, 120.7, 129.2, 129.4, 129.6, 131.3, 132.9, 133.5, 136.0, 139.5, 164.4, 165.5,
173.5, 192.2, 196.7 ppm. Anal. Calcd for C23H21ClN2O3 (408.88): C, 67.56; H, 5.18; N, 6.58. Found: C, 67.72; H,
5.23; N, 6.56%.
3-Hydroxy-2-(1-hydroxy-2,5-diphenyl-1H-imidazol-4-yl)-5,5-dimethylcyclohex-2-en-1-one (5g). mp 188-190
oC. IR ʋ/cm-1 (KBr): 3362, 2952, 1690. 1H NMR (500 MHz, DMSO-d6): δ 1.09 (s, 6H, 2CH3), 2.49 (s, 1H, OH), 2.59
(s, 2H, CH2), 3.18 (s, 2H, CH2), 7.53 (d, J 10.0 Hz, 2H, ArH), 7.54 (d, J 10.0 Hz, 2H, ArH), 7.59 (m, 1H, ArH), 7.67
(m, 1H, ArH), 7.78 (d, J 5.0 Hz, 2H, ArH), 8.41 (d, J 10.0 Hz, 2H, ArH), 14.10 (s, 1H, OH) ppm. 13C NMR (125 MHz,
DMSO-d6): δ 28.1, 32.8, 45.7, 51.5, 120.7, 129.1, 129.2, 129.4, 129.5, 132.8, 134.5, 134.8, 136.1, 164.9, 165.5,
173.4, 193.2, 196.6 ppm. Anal. Calcd for C23H22N2O3 (374.44): C, 73.78; H, 5.92; N, 7.48. Found: C, 73.66; H,
5.91; N, 7.44%.
3-Hydroxy-2-(1-hydroxy-2-phenyl-5-(p-tolyl)-1H-imidazol-4-yl)-5,5-dimethylcyclohex-2-en-1-one (5h). mp
o
1
150-153 C. IR ʋ/cm-1 (KBr): 3450, 2958, 1682. H NMR (500 MHz, DMSO-d6): δ 1.17 (s, 6H, 2CH3), 2.05 (s, 1H,
OH), 2.42 (s, 3H, CH3), 2.55 (s, 2H, CH2), 3.14 (s, 2H, CH2), 7.26 (s, 2H, ArH), 7.50 (m, 2H, ArH), 7.52 (d, J 8.3 Hz,
1H, ArH), 7.72 (d, J 7.0 Hz, 2H, ArH), 8.56 (d, J 7.0 Hz, 2H, ArH), 13.81 (s, 1H, OH) ppm. 13C NMR (125 MHz,
DMSO-d6): δ 21.8, 28.3, 32.7, 46.3, 52.0, 117.2, 120.4, 128.6, 129.4, 129.4, 132.1, 136.1, 138.9, 144.7, 148.5,
165.6, 172.0, 195.5, 197.5 ppm. Anal. Calcd for C24H24N2O3 (388.47): C, 74.21; H, 6.23; N, 7.21. Found: C, 74.37;
H, 6.29; N, 7.18%.
2-(2-(4-Bromophenyl)-5-(4-chlorophenyl)-1-hydroxy-1H-imidazol-4-yl)-3-hydroxy-5,5-dimethylcyclohex-2-
o
1
en-1-one (5i). mp 192-194 C. IR ʋ/cm-1 (KBr): 3425, 2956, 1654. H NMR (500 MHz, DMSO-d6): δ 0.79 (s, 3H,
CH3), 0.81 (s, 3H, CH3), 2.11(s, 2H, CH2), 2.31 (s, 2H, CH2), 2.66 (s, 1H, OH), 7.03 (d, J 8.7 Hz, 2H, ArH), 7.11 (d, J
8.6 Hz, 2H, ArH), 7.42 (d, J 8.7 Hz, 2H, ArH), 7.59 (d, J 8.6 Hz, 2H, ArH), 13.05 (s, 1H, OH) ppm. 13C NMR (125
MHz, DMSO-d6): δ 27.9, 28.0, 30.3, 51.7, 51.9, 104.0, 109.6, 125.1, 126.0, 127.7, 128.3, 129.2, 132.2, 134.1,
136.7, 156.3, 179.0, 199.2, 199.9 ppm.
2-(2-(4-Bromophenyl)-1-hydroxy-5-(p-tolyl)-1H-imidazol-4-yl)-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one
1
(5j). mp 193-195 oC. IR ʋ/cm-1 (KBr): 3432, 2954, 1654. H NMR (500 MHz, DMSO-d6): δ 0.84 (s, 3H, CH3), 0.87
(s, 3H, CH3), 2.12 (s, 3H, CH3), 2.15 (s, 2H, CH2), 2.37 (s, 2H, CH2), 2.54 (s, 1H, OH), 6.92 (d, J 8.0 Hz, 2H, ArH),
7.10 (d, J 8.4 Hz, 2H, ArH), 7.48 (d, J 8.0 Hz, 2H, ArH), 7.66 (d, J 8.4 Hz, 2H, ArH), 13.15 (s, 1H, OH) ppm. 13C NMR
(125 MHz, DMSO-d6): δ 21.0, 28.0, 28.1, 30.3, 51.8, 51.9, 104.6, 109.7, 124.3, 125.4, 127.5, 128.9, 129.1, 132.2,
134.9, 138.3, 155.8, 180.1, 199.1, 200.0 ppm. Anal. Calcd for C24H23BrN2O3 (467.36): C, 61.68; H, 4.96; N, 5.99.
Found: C, 61.70; H, 4.99; N, 6.04%.
2-(2-(4-Bromophenyl)-1-hydroxy-5-phenyl-1H-imidazol-4-yl)-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one
1
(5k). mp 197-199 oC. IR ʋ/cm-1 (KBr): 3433, 2924, 1655. H NMR (500 MHz, DMSO-d6): δ 0.86 (s, 3H, CH3), 0.90
(s, 3H, CH3), 2.18 (s, 2H, CH2), 2.40 (s, 1H, OH), 2.50 (s, 2H, CH2), 7.15 (d, J 5.0 Hz, 2H, ArH), 7.25 (s, 2H, ArH),
7.52 (d, J 5.0 Hz, 2H, ArH), 7.55 (s, 1H, ArH), 7.69 (d, J 7.1 Hz, 2H, ArH), 13.18 (s, 1H, OH) ppm. 13C NMR (125
MHz, DMSO-d6): δ 28.0, 28.0, 30.4, 51.8, 51.9, 104.7, 117.0, 124.4, 127.7, 128.2, 128.5, 129.2, 130.7, 132.2,
132.2, 138.7, 156.0, 180.0, 199.1 ppm.
Page 7
©ARKAT USA, Inc

Arkivoc 2019, vi, 0-0
Alizadeh-Bami, F. et al.
2-(2-(4-Bromophenyl)-1-hydroxy-5-(4-nitrophenyl)-1H-imidazol-4-yl)-3-hydroxy-5,5-dimethyl cyclohex-2-en-
1-one (5l). mp 196-198 oC. IR ʋ/cm-1 (KBr): 3424, 2957, 1660. 1H NMR (500 MHz, DMSO-d6): δ 1.04 (s, 3H, CH3),
1.07 (s, 3H, CH3), 1.18 (s, 1H, OH), 2.35 (s, 2H, CH2), 2.58 (s, 2H, CH2), 7.61 (m, 2H, ArH), 7.68 (d, J 8.1 Hz, 2H,
ArH), 7.83 (d, J 8.1 Hz, 2H, ArH), 8.18 (d, J 8.3 Hz, 2H, ArH), 13.32 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-
d6): δ 28.1, 28.3, 30.6, 51.9, 52.1, 104.0, 109.8, 123.7, 124.9, 125.7, 128.4, 129.3, 132.5, 145.1, 148.0, 157.3,
178.5, 199.5, 200.4 ppm. Anal. Calcd for C23H20BrN3O5 (498.33): C, 55.44; H, 4.05; N, 8.43. Found: C, 55.27; H,
4.01; N, 8.37%.
Supplementary Material
The Experimental Section and the 1H and 13C NMR spectra for compounds 5a-l can be found using the link
"Supplementary Material" in the journal issue contents page.
References
1. Mloston, G.; Jasinski, M.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2006, 89, 1304.
https://doi.org/10.1002/hlca.200690129
2. Nikitina, P. A.; Tkach, I. I.; Knyazhanskaya, E. S.; Gottikh, M. B.; Perevalov, V. P. Pharm. Chem. J. 2016, 50,
513.
https://doi.org/10.1007/s11094-016-1479-x
3. Laufer, S. A.; Zimmermann, W.; Ruff, K. J. J. Med. Chem. 2004, 47, 6311.
https://doi.org/10.1021/jm0496584
4. Harnden, M. R.; Jennings, L. J.; Mckie, C. M.; Parkin, A. Synthesis 1990, 10, 893.
https://doi.org/10.1055/s-1990-27045
5. Khan, M. S.; Siddiqui, S. A.; Siddiqui, M. S.; Goswami, U.; Srinivasan, K. V.; Khan, M. I. Chem. Biol. Drug.
Des. 2008, 72, 197.
https://doi.org/10.1111/j.1747-0285.2008.00691.x
6. Aguirre, G.; Boiani, M.; Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Sainz, Y. F.; Denicola, A.; De Ocariz, C. O.;
Nogal, J. J.; Montero, D.; Escario, J. A. Arch. Pharm. Pharm. Med. Chem. 2004, 337, 259.
https://doi.org/10.1002/ardp.200300840
7. Eriksen, B. L.; Vedso, P.; Begtrup, M. J. Org. Chem. 2001, 66, 8344.
https://doi.org/10.1021/jo001554n
8. Boiani, M.; Gonzalez, M. Mini-Rev. Med. Chem. 2005, 5, 409.
https://doi.org/10.2174/1389557053544047
9. Cerecetto, H.; Gonzalez, M. Curr. Top. Med. Chem. 2002, 2, 1187.
https://doi.org/10.2174/1568026023393066
10. Davila-Jimenez, M. M.; Elizalde-Gonzalez, M. P.; Garcia-Diaz, S. J. Liq. Chromatogr. R. T. 1998, 21, 1629.
https://doi.org/10.1080/10826079808001249
11. Lukomska-Rogala, M.; Rybarczyk-Pirek, A. J.; Ejsmont, K.; Jasinski, M.; Palusiak, M. Struct. Chem. 2017, 28,
1229.
https://doi.org/10.1007/s11224-017-0935-x
Page 8
©ARKAT USA, Inc

Arkivoc 2019, vi, 0-0
Alizadeh-Bami, F. et al.
12. Begtrup, M. Adv. Heterocycl. Chem. 2012, 106, 1.
https://doi.org/10.1016/B978-0-12-396531-8.00001-8
13. Rybarczyk-Pirek, A. J.; Lukomska, M.; Ejsmont, K.; Jasinski, M.; Palusiak, M. Struct. Chem. 2014, 25, 979.
https://doi.org/10.1007/s11224-014-0404-8
14. Mloston, G.; Gendek, T.; Heimgartner, H. Helv. Chim. Acta 1998, 81, 1585.
https://doi.org/10.1002/(SICI)1522-2675(19980909)81:9<1585::AID-HLCA1585>3.0.CO;2-N
15. Jasinski, M.; Mloston, G.; Mucha, P.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2007, 90, 1765.
https://doi.org/10.1002/hlca.200790186
16. Antonova, M. M.; Baranov, V. V.; Nelyubina, Y. V.; Kravchenko, A. N. Chem. Heterocycl. Comp. 2014, 50,
1203.
https://doi.org/10.1007/s10593-014-1583-3
17. Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Sainz, Y. F.; Piro, O. E.; Castellano, E. E. Synthesis 2004, 16, 2678.
https://doi.org/10.1055/s-2004-831212
18. Alcazar, J.; Begtrup, M.; De La Hoz, A. J. Chem. Soc. 1995, 19, 2467.
https://doi.org/10.1039/p19950002467
19. Mloston, G.; Celeda, M.; Prakash, G. S.; Olah, G. A.; Heimgartner, H. Helv. Chim. Acta 2000, 83, 728.
https://doi.org/10.1002/(sici)1522-2675(20000412)83:4<728::aid-hlca728>3.0.co;2-b
20. Volkamer, K.; Zimmermann, H. W. Chem. Ber. 1969, 102, 4177.
https://doi.org/10.1002/cber.19691021225
21. Kuruba, B. K.; Vasanthkumar, S.; Emmanuvel, L. Synth. Commun. 2016, 46, 799.
https://doi.org/10.1080/00397911.2016.1176200
22. Rajkumar, R.; Kamaraj, A.; Krishnasamy, K. Journal of Taibah University for Science. 2015, 9, 498.
https://doi.org/10.1016/j.jtusci.2014.12.001
23. Hasaninejad, A., Zare, A., Shekouhy, M.; Ameri-Rad, J. J. Comb. Chem. 2010, 12, 844.
https://doi.org/10.1021/cc100097m
24. Sharma, S. D.; Hazarika, P.; Konwar, D. Tetrahedron Lett. 2008, 49, 2216.
https://doi.org/10.1016/j.tetlet.2008.02.053
25. Gandhare, N. V.; Chaudhary, R.G.; Meshram, V. P.; Tanna, J. A.; Lade, S.; Gharpure, M. P.; Juneja, H. D. J.
Chin. Adv. Mater. Soc. 2015, 3, 270.
https://doi.org/10.1080/22243682.2015.1068134
26. Yugandar, S.; Konda, S.; Parameshwarappa, G.; Ila, H. J. Org. Chem. 2016, 81, 5606.
https://doi.org/10.1021/acs.joc.6b00938
27. Mehrabi, H.; Alizadeh-Bami, F.; Ranjbar-Karimi, R. J. Iran. Chem. Soc. 2018, 15, 1961.
https://doi.org/10.1007/s13738-018-1393-0
28. Mehrabi, H.; Najafian-Ashrafi, F.; Ranjbar-Karimi, R. Arkivoc 2018, (iii), 191.
https://doi.org/10.24820/ark.5550190.p010.404
Page 9
©ARKAT USA, Inc