Synthesis of imidazole derivatives: Ester and hydrazide compounds with antioxidant activity using ionic liquid as an efficient catalyst

Article abstract of DOI:10.1002/jhet.3808

The pyrrolidinium hydrogen sulfate (PHS) was used as an excellent ionic liquid catalyst for the preparation of many imidazoles moiety, which have biologically application via one-pot multicomponent reaction. Imidazoles were afforded through the reaction o

Full text of DOI:10.1002/jhet.3808

Received: 19 April 2019
DOI: 10.1002/jhet.3808
Revised: 17 September 2019
Accepted: 8 October 2019
A R T I C L E
Synthesis of imidazole derivatives: Ester and hydrazide
compounds with antioxidant activity using ionic liquid as an
efficient catalyst
Antar A. Abdelhamid1
| Hanan A. Salah1 | Adel A. Marzouk2
1 Chemistry Department, Faculty of
Science, Sohag University, Sohag, Egypt
Abstract
The pyrrolidinium hydrogen sulfate (PHS) was used as an excellent ionic liquid
catalyst for the preparation of many imidazoles moiety, which have biologically
application via one‐pot multicomponent reaction. Imidazoles were afforded
through the reaction of equimolar from 1,2‐diphenylethane‐1,2‐dione, ammo-
nium acetate, different aromatic aldehydes, and ethyl glycinate hydrochloride.
This method has the advantages of giving excellent yield, shortened reaction
times, and ease of establishment. Moreover, the yielded of imidazoles compo-
nents can be purified and crystallized by a nonchromatographic technique,
and the catalyst can be reused. These entire novel synthesized components
have been identified by spectral data: IR, NMR and mass spectra. These com-
pounds have an in vivo antioxidant activity on experimental animals (rats).
2 Pharmaceutical Chemistry Department,
Faculty of Pharmacy, Al Azhar University,
Cairo, Egypt
Correspondence
Antar A. Abdelhamid, Chemistry
Department, Faculty of Science, Sohag
University, Sohag 82524, Egypt.
Email: drantar25@yahoo.com
1 | INTRODUCTION
Al2O3,[11] HY/silicagel,[12] NiCl2.6H2O,[13] iodine[14] and
Yb (OTf)3,[15] and boric acid using ultrasound irradiation,[16]
Through the last few years, the preparation of imidazole
derivatives had a great attention in synthetic organic chem-
istry because of comprehensive abundance of applications
in the industrial, pharmaceutical, and medicinal chemis-
try.[1] Moreover, they have various biological applications
such as analgesic, antiallergic, antibacterial, antifungal,
anthelmintic, antiprotozoal, anti‐inflammatory, and anti-
tuberculosis activity.[2–4] These imidazole derivatives nor-
mally found in multiple forms such as Olmesartan and
Losartan.[5]
Owing to the versatile biological activities of substituted
imidazoles, several classical methods for their synthesis
have been reported.[6–9] In a typical procedure, benzil or
benzoin, aldehydes, amines, and ammonium acetate are
used in the presence of strong protic acid and organo
catalyst. These homogeneous catalysts have limitations
due to the use of corrosive reagents, polar organic
solvents, and the necessity of neutralization of the strong
acid media.[10] More several modifications were then
introduced to the classical procedure using acidic
and potassium dihydrogen phosphate.[17] However, all are
plagued by the limitations of poor yield, longer reaction
time, difficult work‐up, and effluent pollution. Therefore,
the development of a new mild method to overcome these
disadvantages was necessary.[18]
In recent years, environmentally friendly reaction pro-
cesses have been strongly studied from the green chemistry
point of view. Scientists paid great attention to ionic liquids
as green reaction solvents used in organic synthesis and
introduced as a favorable alternative.[19] Ionic liquid is
defined as lucid organic salts, which have melting point
below 100°C and quieted completely of ions.[20] They con-
sist of inorganic anions and organic cations where appro-
priate combination of cation and anion can strengthen
the polarity and hydrophilicity/hydrophobicity of ionic liq-
uids.[21–25] Their application extensively reviewed as cata-
lytic phase in diverse organometallic reactions.[26] Beside
employment of ionic liquids as alternate solvents, lately,
further work has supported the new functionality of ionic
liquids, which referred to as “task specific ionic liquids”
J Heterocyclic Chem. 2019;1–10.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
ABDELHAMID ET AL.
(TSIL). This attempt introduced the ionic liquids as a true
working system in the reaction rather than just reaction
media.[27,28]
and further increase were not beneficial to the process
(Table 2).
The possible mechanism of the one‐pot multicompo-
nent cyclocondensation of 1,2‐diphenylethane‐1,2‐dione,
ethyl glycinate and the convenient aromatic aldehyde
together with ionic liquid, in the presence of 1 mol of
ammonium acetate contains a key coupling step of the
intermediate of benzaldehyde imine (I). On the other hand,
ethyl glycinate attack the activated benzil to form α‐imino
ketone (II). This is followed by the nucleophilic attack of
the in situ generated imine to carbonyl of aryl ketoimine
giving the intermediate (III). Their subsequent intramolec-
ular interaction leads to cyclization and eventually to the
formation of intermediate (IV), which dehydrates to the
1,2,4,5‐tetrasubstituted imidazole (Scheme 2).
Herein, a simple, highly versatile, and efficient synthe-
sis of tetrasubstituted imidazoles is achieved by four com-
ponent cyclocondensation of 1,2‐dicarbonyl compounds,
aldehydes, primary amine, and ammonium acetate in
thermal and solvent free condition using acidic ionic liq-
uid pyrrolidinium hydrogen sulfate (PHS) as a catalyst.
The advantages of PHS are cost effectiveness, reusability,
nonflammability, high viscosity, thermal and oxidative
stability, good solvation power, nonvolatility, and being
ecofriendly catalyst.[29] The key advantages of this
process are cost effectiveness of catalyst, reusability of
catalyst, easy work‐up and purification of products by
nonchromatographic methods, excellent yields, and very
short time reactions (20‐50 minutes).[30]
2.1 | Antioxidant activity
2 | RESULTS AND DISCUSSION
The antioxidant activities of the present compounds were
determined using some oxidative stress biomarker assays.
They included plasma malondialdehyde level (MDA),
liver reduced glutathione content (GSH) and nitric oxide
level (NO) in vivo on rats. All these oxidative stress bio-
markers showed remarkable differences with all tested
compounds. The most increased value of MDA level was
recorded with compound 5a, and the most decreased
one was recorded with compound 7 in comparing with
the control value (Figure 1A). The most increased value
of liver GSH level is determined with 5b, and the most
decreased value is recorded with 5a and 5e, respectively,
as compared with control value (Figure 1B). Compounds
5b and 7 displayed the most increased effect of NO level;
however, compound 5a caused the most decreased effect
as compared with control value (Figure 1C).
Regard to previous literature review, we are found that
imidazoles derivatives have pharmaceutical and biologi-
cal activity.[31] So, we are decided to research the capacity
of the ionic liquid for preparation of multisubstitute
dimidazoles (5) in a good yield. The reaction between
1,2‐diphenylethane‐1,2‐dione (1), aromatic aldehydes
(2a‐h), ammonium acetate (3), and ethyl glycinate (4) in
the presence of ionic liquid was illustrated in (Scheme 1,
Table 1). All the novel components are checked with IR
and NMR analysis. The method was found to be simple,
expeditious, and environmentally friendly.
To the improvement of the reaction condition opti-
mized, we investigated the model reaction further by dif-
ferent of the amount of the ionic liquid catalyst. We are
noted that 4 mol % gave the highest products of 96%,
SCHEME 1 Optimization of the
synthesis of 1,2,4,5‐tetrasubstituted
imidazoles 5a‐h, 6a‐h, and 7

ABDELHAMID ET AL.
3
TABLE 1 List of 1,2,4,5‐tetrasubstituted imidazole derivatives formed after addition of acidic ionic liquid pyrrolidinium hydrogen sulfate
(PHS) (5a‐h), after addition of hydrazine hydrate (6a‐h), and after addition of isatin (7)
No
5a
Formula, Mol. wt.
Scheme
M.P., °C
Reaction Time, min
Yield, %
C25H21ClN2O2 (416.19)
121‐123
37
96
5b
5c
C26H24N2O3 (412.48)
114‐116
151‐153
44
38
92
90
C25H22N2O3 (398.45)
5d
C25H20Cl2N2O2 (451.34)
124‐126
44
88
5e
C26H24N2O3 (412.48)
115‐116
43
94
5f
C23H20N2O2S (388.48)
C26H24N2O4 (428.48)
C27H27N3O2 (425.52)
124‐125
112‐114
114‐115
55
48
55
94
5 g
92
5 h
93
(Continues)

4
ABDELHAMID ET AL.
TABLE 1 (Continued)
No
Formula, Mol. wt.
Scheme
M.P., °C
Reaction Time, min
Yield, %
6a
6b
6c
6d
C23H19ClN4O (402.88)
C24H22N4O2 (398.46)
C23H20N4O2 (384.43)
C23H18Cl2N4O (435.35)
115
17
20
25
33
88
95
96
95
88‐90
120‐122
113‐114
6e
C23H20N4O (368.43)
C21H18N4OS (374.46)
C24H22N4O3 (414.46)
110
35
21
33
91
6f
111‐112
113‐115
97
6 g
91
(Continues)

ABDELHAMID ET AL.
5
TABLE 1 (Continued)
No
6 h
Formula, Mol. wt.
Scheme
M.P., °C
Reaction Time, min
Yield, %
C25H25N5O (411.50)
109‐110
45
89
7
C31H22ClN5O2 (531.99)
154‐156
25
93
monitored by thin‐layer chromatography (TLC), the mix-
ture washed with water, the solid product purified by
recrystallization from ethanol or methanol. While the
ionic liquid in the filtrate can be regained after evaporat-
ing all solvents till oily mass of ionic liquid collected,
ionic liquid now can be reused later for more reactions.
2.2 | Experimental
2.2.1 | General methods for synthesis of
PHS ionic liquid
Pyrrolidine (20 mmol) was added in the three‐necked
rounded bottom flask (150 mL), which have a magnetic
stirrer. An equimolar concentrated H2SO4 was added
slowly in a drop wise manner into this the flask at 0°C.After
that, the reaction mixture was allowed to be stirred and
heated at 80°Cfor 12 hours. Diethyl ether was used three
times for washing the reaction mixture to expel the
nonreacted compounds (nonionic residues) and dry using
the rotary evaporator to acquire the viscous pure PHS.[32]
2.2.3 | General method for the synthesis of
2‐(2‐(substituted)‐4,5‐diphenyl‐1H‐imidazol‐
1‐yl)acetohydrazide (6a‐h)
To a solution of ethyl 4,5‐diphenyl‐2‐(substituted)‐1H‐
imidazole‐1‐carboxylate 5a‐h (5 mmol) in ethanol, hydra-
zine hydrate (5.1 mmol, 100%) was added slowly with
persistent stirring. The reaction mixture allowed to reflux
for 3 hours and cooled at 25°C. The separated product
was collected with filtration, dried, and crystallized from
methanol or ethanol.
2.2.2 | General method for the synthesis of
ethyl4,5‐diphenyl‐2‐(substituted)‐1H‐imid-
azole‐1‐carboxylate (5a‐h)
A mixture of 20‐mmol aromatic aldehydes, 20‐mmol 1,2‐
diphenylethane‐1,2‐dione, 20‐mmol ammonium acetate,
and 20‐mmol ethyl glycinate were added to 4 mol %
PHS ionic liquid as a catalyst. The reaction mixture was
allowed toreflux foran appropriate time according to
Table 1. After completion of the reaction, which was
2.3 | Animal treatment and experimental
design
Male rats of body weight (160‐180 g) were obtained from
animal house, Sohag University, Egypt. They were housed
and preserved on standard laboratory diet and water.
y
TABLE 2 The amount of pyrrolidinium hydrogen sulphate catalyst for synthesis of imidazoles (MSI) 5x
Entry
Catalysts/mol %b
Yield, %a
Entry
Catalysts/mol %b
Yield, %a
5a
5a
5a
1
2
3
44
68
73
5a
5a
5a
4
5
6
96
96
96
aIsolated yields based on 5a.
bAmount of catalyst used: 1, 2, 3, 4, 5, and 6 mol % catalyst.

6
ABDELHAMID ET AL.
SCHEME 2 The suggested mechanism
of prepared multisubstitute dimidazoles
(MSI) 5a‐h
Animals were categorized into three groups, each contain-
ing 6 to 8 animals. The first one (control) was received
dimethyl sulfoxide (DMSO); however, methotrexate injec-
tion (7 mg/kg) was given intraperitoneally (i.p) daily for
three sequential days to the positive control group. The
third group was given tested compounds (150 mg/kg) dis-
solved in DMSO 1 hour before methotrexate daily for three
consecutive days. After 24 hours from the last methotrexate
injection, animals were anesthetized and dissected. Blood
samples were collected via direct cardiac puncture, then
centrifuged for 10 minutes at 3000 g to obtain sera. Livers
were separated, homogenized in potassium phosphate
buffer (0.05M, pH 7.4) and frozen at −20°C for analy-
sis.[33,34] Animals handling and care was corresponding to
the ethical standards confirmed by the Institutional Ani-
mal Ethics Committee guidelines, Sohag University, Egypt.
3. NO determination of:
NO was estimated from plasma spectrophotometrically
using sodium nitrite as a standard according to Griess
reaction.[37]
2.4.1 | Ethyl 2‐(2‐(4‐chlorophenyl)‐4,5‐
diphenyl‐1H‐imidazol‐1‐yl)acetate (5a)
Yield 96%; m.p. 121‐123°C; IR (λ max, cm−1): 3024
(CHarom.), 2944‐2898 (CHaliph.), 1735 (C═O), 1608
(C═N);1H‐NMR (DMSO‐d6), δ ppm: 7.72‐7.15 (m,14H,
CHarom.), 4.66 (s, 2H, CH2‐C═O), 4.00 (q, 2H, OCH2CH3),
1.01 (t, 3H, OCH2CH3); 13C‐NMR (DMSO‐d6), δ ppm:
168.65, 146.71, 137.17, 134.61, 131.24, 130.74, 130.45,
129.72, 129.57, 129.33, 128.61, 126.92, 126.55, 61.85,
47.22, 14.23 ppm. Elemental Analysis: Calcd. C, 72.02;
H, 5.08; N, 6.72. Found: 72.00; H, 5.02; N, 6.71.
2.4 | Antioxidant assays
1. Thiobarbituric acid reactive substance (MDA)
determination:
2.4.2 | Ethyl 2‐(2‐(4‐methoxyphenyl)‐4,5‐
diphenyl‐1H‐imidazol‐1‐yl)acetate (5b)
Determination of thiobarbituric acid reactive sub-
stances from the hepatic tissues was performed by using
the method of Uchiyama and Mihara,[35] it was colorimet-
ric calculated as MDA, which was applied based on the
reaction of one molecule of MDA with two molecules of
thiobarbituric acid.
Yield 92%; m.p. 114‐116°C; IR (λ max, cm−1): (CHarom.
)
1
3055, 2955‐2880 (CHaliph.), 1735 (C═O), 1605 (C═N); H‐
NMR (DMSO‐d6), δ ppm: 7.16‐7.18 (m, 14H, CHarom.),
4.60 (s, 2H, CH2‐C═O), 4.02 (q, 2H, OCH2CH3), 3.82 (s,
3H, OCH3), 1.02 (t, 3H, OCH2CH3); 13C‐NMR (DMSO‐
d6) δ ppm: 168.81, 160.32, 147.81, 136.73, 134.89, 131.26,
130.78, 130.48, 130.14, 130.05, 129.96, 129.66, 129.57,
128.56, 126.74, 126.52, 123.06, 114.65, 61.78, 55.71, 47.14,
14.26; DEPT 135 (300 MHz, DMSO‐d6): 61.78, 55.71
(CH2) ppm disappeared. Elemental Analysis: Calcd. C,
75.71; H, 5.86; N, 6.79. Found: 75.69; H, 5.83; N, 6.75.
2. Reduced GSH determination of:
Liver GSH was determined spectrophotometrically
according to the method of Beutler et al.[36] Reduced
GSH was used as a standard.

ABDELHAMID ET AL.
7
128.82, 128.63, 128.11,127.51, 127.12, 126.90, 115.18,
65.14, 61.15, 14.53; DEPT 135 (300 MHz, DMSO‐d6):
65.14, 61.15 (CH2) ppm disappeared. Elemental Analysis:
Calcd. C, 75.36; H, 5.57; N, 7.03, Found: C, 75.34; H, 5.53;
N, 7.00.
2.4.4 | Ethyl 2‐(2‐(2,6‐dichlorophenyl)‐4,5‐
diphenyl‐1H‐imidazol‐1‐yl)acetate (5d)
Yellow crystals; yield 88%; m.p. 124‐126°C; IR (λ max,
cm−1): 3033 (CHarom.), 2933‐2814 (CHaliph.), 1740
(C═Oester), 1600 (C═N); 1H‐NMR (DMSO‐d6), δ ppm:
7.95‐7.21 (m, 13H, CHarom.), 4.65 (s, 2H, CH2‐C═O), 4.01
(q, 2H, OCH2CH3), 1.03 (t, 3H, OCH2CH3); 13C‐NMR
(DMSO‐d6), δ ppm: 197.33, 168.65, 160.43, 147.12,
137.76, 134.71, 134.24, 130.76, 130.07, 130.01, 129.99,
129.69, 128.61, 121.63, 118.11, 117.95, 117.12, 63.17,
57.75, 43.23, 13.56 ppm. Elemental Analysis: Calcd. C,
66.53; H, 4.47; N, 6.21, Found: C, 66.49; H, 4.46; N, 6.19.
2.4.5 | Ethyl 2‐(2‐(3‐methoxyphenyl)‐4,5‐
diphenyl‐1H‐imidazol‐1‐yl)acetate (5e)
Yield 94%; m.p. 115‐116°C; IR (λ max, cm−1): 3041
(CHarom.), 2934‐2864 (CHaliph.), 1754 (C═Oester), 1605
1
(C═N); H‐NMR (DMSO‐d6), δ ppm:7.95‐7.09 (m, 14H,
CHarom.), 4.65 (s, 2H, CH2‐C═O), 4.02 (q, 2H, OCH2CH3),
3.85 (s, 3H, OCH3), 1.02 (t, 3H, OCH2CH3); 13C‐NMR
(DMSO‐d6), δ ppm: 197.34,169.64, 160.53, 148.13, 138.12,
137.76, 134.71, 134.24, 131.27, 130.06, 130.02, 129.99,
129.69, 128.61, 126.55, 120.12, 118.11, 117.95, 117.12,
115.41, 61.81, 55.66, 47.23, 40.20, 14.25; DEPT 135
(300 MHz, DMSO‐d6): 61.81, 40.20 (CH2) ppm disap-
peared. Elemental Analysis: Calcd. C, 75.71; H, 5.86; N,
6.79, Found: C, 75.70; H, 5.83; N, 6.75.
2.4.6 | Ethyl 2‐(2‐(thiophen‐2‐yl)‐4,5‐
diphenyl‐1H‐imidazol‐1‐yl)acetate (5f)
Yield 73%; m.p. 210‐212°C; IR (λ max, cm−1): 3059
(CHarom.), 2935 (CHaliph.), 1740 (C═O), 1601 (C═N); H‐
FIGURE 1 Antioxidant effects of imidazoles
1
NMR (DMSO‐d6), δ ppm: 7.71‐7.16 (m, 13H, CHarom.),
3.38 (s, 2H, CH2‐C═O), 3.36 (q, 2H, OCH2CH3), 1.09
2.4.3 | Ethyl 2‐(2‐(4‐hydroxyphenyl)‐4,5‐
diphenyl‐1H‐imidazol‐1‐yl)acetate (5c)
(t, 3H, OCH2CH3); 13C‐NMR (DMSO‐d6),
δ ppm:
Yellow crystals; yield 90%; m.p. 151‐153°C; IR (λ max,
cm−1): 3123 (OH), 3042 (CHarom.), 2954‐2865 (CHaliph.),
1739 (C═Oester), 1593 (C═N); 1H‐NMR (DMSO‐d6), δ
ppm: 12.53 (s, 1H, OH), 8.03‐7.04 (m, 14H, CHarom.),
4.85 (s, 2H, CH2‐C═O), 4.23 (q, 2H, OCH2CH3), 1.24
(t, 3H, OCH2CH3); 13C‐NMR (DMSO‐d6), δ ppm: 168.66,
159.33, 148.72, 135.17, 134.61, 131.24,,130.77, 129.11,
196.33,168.61, 161.55, 149.13, 140.13, 137.55, 136.34,
135.34, 136.25, 132.13, 130.02, 129.15, 128.15, 127.60,
125.14, 119.11, 117.09, 116.91, 114.11, 113.10, 60.09,
54.45, 44.20, 41.19, 14.12; DEPT 135 (300 MHz, DMSO‐
d6): 60.09 (CH2) ppm disappeared. Elemental Analysis:
Calcd. C, 71.11; H, 5.19; N, 7.21; S, 8.25, Found: 71.09;
H, 5.14; N, 7.18; S, 8.23.

8
ABDELHAMID ET AL.
2.4.7 | Ethyl 2‐(2‐(4‐hydroxy‐3‐
methoxyphenyl)‐4,5‐diphenyl‐1H‐imidazol‐
1‐yl)acetate (5g)
2.4.10 | 2‐(2‐(4‐Methoxyphenyl)‐4,5‐
diphenyl‐1H‐imidazol‐1‐yl)acetohydrazide
(6b)
Yield 88%; m.p. 112‐114°C; IR (λ max, cm−1): 3341
(OHphenolic), 3045 (CHarom.), 2941‐2844 (CHaliph.), 1721
(C═Oester), 1601 (C═N); 1H‐NMR (DMSO‐d6), δ ppm:
90.14 (br, 1H, OHphenolic) 7.91‐7.12 (m, 13H, CHarom.),
4.61 (s, 2H, CH2‐C═O), 4.00 (q, 2H, OCH2CH3), 3.90
(s, 3H, OCH3), 1.00 (t, 3H, OCH2CH3); 13C‐NMR
(DMSO‐d6), δ ppm: 197.34,169.64, 160.53, 148.13, 138.12,
137.76, 134.71, 134.24, 131.27, 130.06, 130.02, 129.99,
129.69, 128.61, 126.55, 120.12, 118.48, 117.84, 117.17,
115.26, 61.19, 55.14, 48.20, 47.23, 40.22, 14.21; DEPT 135
(300 MHz, DMSO‐d6): 61.81, 40.20 (CH2) ppm disap-
peared. Elemental Analysis: Calcd. C, 72.88; H, 5.65; N,
6.54, Found: C, 72.85; H, 5.62; N, 6.51.
Crystallized as crystals brown color from methanol; yield
95%; m.p. 88‐90°C; IR (λ max, cm−1): 3470, 3315, 3111
(NH, NH2), 3045, 3010 (CHarom.), 2931 (CHaliph.), 1660
1
(C═O), 1610 (C═N); H‐NMR (DMSO‐d6), δ ppm: 9.13
(s, 1H, NH), 7.76‐7.16 (m, 14H, CHarom.), 4.37 (s, 2H,
CH2‐C═O), 4.33 (s, 2H, NH2), 3.8 (s, 3H, OCH3); 13C‐
NMR (DMSO‐d6), δ ppm: 167.99, 148.47, 138.91, 137.13,
135.33, 131.28, 131.19, 130.84, 129.57, 129.14 128.57
126.75, 126.55, 46.58 ppm; DEPT 135 (300 MHz, DMSO‐
d6): 46.58 (CH2) ppm disappeared. Elemental Analysis:
Calcd. C, 72.34; H, 5.57; N, 14.06, found C, 72.33; H,
5.54; N, 14.02.
2.4.11 | 2‐(2‐(4‐Hydroxyphenyl)‐4,5‐
diphenyl‐1H‐imidazol‐1‐yl)acetohydrazide
(6c)
2.4.8 | Ethyl 2‐(2‐(4‐(dimethylamino)phe-
nyl)‐4,5‐diphenyl‐1H‐imidazol‐1‐yl)acetate
(5h)
Crystallized as pale yellowish crystals from DMF; yield
96%; m.p. 120‐122°C; IR (λ max, cm−1): 3472, 3324, 3200
(OH) (NH, NH2), 3067‐3013 (CHarom.), 2975 (CHaliph.),
Yield 92%; m.p. 114‐115°C; IR (λ max, cm−1): (CHarom.
)
3050, 2951‐2885 (CHaliph.), 1741 (C═O), 1609 (C═N);
1H‐NMR (DMSO‐d6), δ ppm: 7.51‐6.69 (m, 14H, CHarom.),
4.61 (s, 2H, CH2‐C═O), 4.30 (q, 2H, OCH2CH3), 2.95 (s,
6H, N (CH3)2), 1.01 (t, 3H, OCH2CH3); 13C‐NMR
(DMSO‐d6) δ ppm: 169.80, 163.14, 147.24, 136.12,
136.01, 134.16,132.72,130.48, 130.51, 130.05, 129.45,
129.02, 128.51, 126.74, 126.52, 123.06, 114.65, 61.78,
55.71, 40.26, 47.14, 14.26; DEPT 135 (300 MHz, DMSO‐
d6): 61.78, 55.71 (CH2) ppm disappeared. Elemental
Analysis: Calcd. C, 76.21; H, 6.40; N, 9.87, found C,
76.18; H, 6.36; N, 9.85.
1
1637 (C═O), 1610 (C═N); H‐NMR (DMSO‐d6), δ ppm:
12.55 (s, 1H, OH), 9.42 (s, 1H, NH), 8.04‐7.07 (m, 14H,
CHarom.), 4.57 (s, 2H, CH2‐C═O), 4.35 (s, 2H, NH2); 13C‐
NMR (DMSO‐d6), δ ppm: 167.04, 157.45, 146.88, 142.14,
138.91, 137.13, 129.10, 128.81, 128.64 127.55, 127.11,
126.12, 115.20, 66.78 ppm; DEPT 135 (300 MHz, DMSO‐
d6): 66.78 (CH2) ppm disappeared. Elemental Analysis:
Calcd. C, 71.86; H, 5.24; N, 14.57, found C, 71.84; H,
5.22; N, 14.54.
2.4.12 | 2‐(2‐(2,6‐Dichlorophenyl)‐4,5‐
diphenyl‐1H‐imidazol‐1‐yl)acetohydrazide
(6d)
2.4.9 | 2‐(2‐(4‐chlorophenyl)‐4,5‐diphenyl‐
1H‐imidazol‐1‐yl)acetohydrazide (6a)
Crystalized as brown crystals from methanol; yield 89%;
m.p. 115°C; IR (λ max, cm−1): 3471, 3321, 3220 (NH,
NH2), 3041,3012 (CHarom.), 2941 (CHaliph.), 1665 (C═O),
Crystallized as brownish crystal from methanol; yield
95%; m.p. 113‐114°C; IR (λ max, cm−1): 3024 (CHarom.),
1
2944‐2898 (CHaliph.), 1639 (C═O), 1606 (C═N); H‐NMR
1
1608 (C═N); H‐NMR (DMSO‐d6), δ ppm: 9.13 (s, 1H,
(DMSO‐d6), δ ppm: 9.34 (s, 1H, NH), 7.98‐7.00 (m, 13H,
CHarom.), 4.63 (s, 2H, CH2‐C═O), 4.25 (s, 2H, NH2); 13C‐
NMR (DMSO‐d6), δ ppm: 168.65, 146.71, 137.17, 134.61,
131.24,,130.74, 130.45, 129.72, 129.57, 129.33, 128.61,
126.92, 126.55, 61.85 ppm; DEPT 135 (300 MHz, DMSO‐
d6): 61.85 (CH2) ppm disappeared. Elemental Analysis:
Calcd. C, 63.17; H, 4.15; N, 12.81, found C, 63.15; H,
4.12; N, 12.77.
NH), 7.76‐7.14 (m, 14H, CHarom.), 4.37 (s, 2H, CH2‐
C═O), 4.33 (s, 2H, NH2); 13C‐NMR (DMSO‐d6), δ ppm:
167.65, 148.14, 138.91, 137.13, 135.33, 131.28, 131.19,
130.84, 129.57, 129.14 128.57 126.75, 126.55, 46.58 ppm;
DEPT 135 (300 MHz, DMSO‐d6): 46.58 (CH2) ppm disap-
peared. Elemental Analysis: Calcd. C, 68.57; H, 4.75; N,
13.91, found C, 68.55; H, 4.72; N, 13.88,

ABDELHAMID ET AL.
9
2.4.13 | 2‐(2,4,5‐triphenyl‐1H‐imidazol‐1‐yl)
acetohydrazide (6e)
2.4.16 | 2‐(2‐(4‐(dimethylamino)phenyl)‐
4,5‐diphenyl‐1H‐imidazol‐1‐yl)
acetohydrazide (6h)
Yield 90%; m.p. 110°C; IR (λ max, cm−1):, 3454, 3354,
3210 (NH, NH2), 3033 (CHarom.), 2991 (CHaliph.), 1664
(C═O), 1604 (C═N);1H‐NMR (DMSO‐d6), δ ppm: 9.06
(s,1H,NH), 8.12‐7.14 (m,15H,CHarom.), 4.38 (s,2H,
CH2aliph.), 4.25 (s, 2H, NH2); 13C‐NMR (DMSO‐d6), δ
ppm: 191.31,165.11, 164.12, 148.45, 141.54, 139.18,
137.41, 135.34, 136.25, 135.21, 132.13, 130.02, 129.15,
128.15, 127.60, 125.14, 119.11, 117.09, 116.91, 114.11,
113.10, 61.10; DEPT 135 (300 MHz, DMSO‐d6): 61.10
(CH2) ppm disappeared. Elemental Analysis: Calcd. C,
74.98; H, 5.47; N, 15.21, found. C, 74.95; H, 5.44; N,
15.18.
Yield 90%; m.p. 109°C; IR (λ max, cm−1): 3350 (broad
NH + NH2), 3030 (CHarom.), 2925‐2801 (CHaliph.), 1672
(C═O), 1611 (C═N); H‐NMR (DMSO‐d6), δ ppm: 9.10
(s, 1H, NH); 7.95‐6.80 (m, 14H, CHarom.); 4.35 (s, 2H,
CH); 4.00 (s, 2H, NH2); 2.97 (s, 6H, 2CH3); 13C‐NMR
(DMSO‐d6), δ ppm: 188.91, 167.91, 148.14, 139.90,
136.53, 137.32, 130.17, 130.09, 130.01, 129.99, 129.19
128.17, 127.27, 126.23, 46.54, 45.12 ppm; DEPT 135
(300 MHz, DMSO‐d6): 46.54 (CH2) ppm disappeared. Ele-
mental Analysis: Calcd. C, 72.97; H, 6.12; N, 17.02, found
C, 72.95; H, 6.10; N, 17.00.
1
2.4.17 | 2‐(2‐(4‐chlorophenyl)‐4,5‐diphenyl‐
1H‐imidazol‐1‐yl)‐N′‐(2‐oxoindolin‐3‐yli-
dene)acetohydrazide (7)
2.4.14 | 2‐(4,5‐diphenyl‐2‐(thiophen‐2‐yl)‐
1H‐imidazol‐1‐yl)acetohydrazide (6f)
Yield 93%; m.p. 228°C; crystalized as brownish crystals
from methanol; yield 93%; m.p. 154‐156°C; IR (λ max,
cm−1): 3317, 3161 (2NH), 3045‐3010 (CHarom.), 2976
(CHaliph.), 1675, 1666 (2 C═O), 1608 (C═C); 1H‐NMR
(DMSO‐d6), δ ppm: 12.7, 11.44 (s, 2H, 2NH.), 7.82‐6.96
(m, 18H, CHarom.), 5.21 (s, 2H, CH2‐C═O);13C‐NMR
(DMSO‐d6), δ ppm: 197.33, 188.31, 168.65, 167.51,
164.44, 160.43, 157.61, 147.12, 145.44, 137.76, 134.71,
134.24,,130.76, 130.07, 130.01, 129.99, 129.69, 128.61,
121.63, 118.11, 117.95, 117.12, 63.14 ppm. Elemental
Analysis: Calcd. C, 69.99; H, 4.17; N, 13.16, found C,
69.95; H, 4.14; N, 13.12.
Yield 97%; m.p. 111‐112°C; IR (λ max, cm−1): 3314,
3212, 3111 (NH, NH2), 3012 (CHarom.), 2934 (CHaliph.),
1
1671 (C═O), 1602 (C═N); H‐NMR (DMSO‐d6), δ ppm:
9.25 (s,1H,NH), 7.70‐7.16 (m,13H,CHarom.), 4.49 (s, 2H,
CH2aliph.), 4.34 (s, 2H, NH2); 13C‐NMR (DMSO‐d6), δ
ppm: 191.31,165.11, 164.12, 148.45, 141.54, 139.18,
137.41, 135.34, 136.25, 135.21, 132.13, 130.02, 129.15,
128.15, 127.60, 125.14, 119.11, 117.09, 116.91, 114.11,
113.10, 61.10, 54.45, 44.20, 41.19, 15.14; DEPT 135
(300 MHz, DMSO‐d6): 61.10 (CH2) ppm disappeared.
Elemental Analysis: Calcd. C, 67.36; H, 4.85; N, 14.96;
S, 8.56, found C, 67.33; H, 4.84; N, 14.93; S, 8.54.
3 | CONCLUSION
2.4.15 | 2‐(2‐(4‐hydroxy‐3‐methoxyphenyl)‐
4,5‐diphenyl‐1H‐imidazol‐1‐yl)
acetohydrazide (6g)
Series of imidazole derivatives were synthesized by using
the good catalyst PHS through a multicomponent reac-
tion. The reaction was carried out in short time, giving
very high yield products, as compounds (5a and 6f; 96%
and 97%) respectively, that have in vivo antioxidant activ-
ity on experimental animals (rats).
Yield 92%; m.p. 113‐115°C; IR (λ max, cm−1): 3500
(OHbroad), 3305‐3200 (NH+NH2), 3061 (CHarom.), 2938
(CHaliph.), 1673(C═O), 1602 (C═N); 1H‐NMR (DMSO‐
d6), δ ppm: 12.51 (s, 1H, OH), 9.33 (s, 1H, NH),7.72‐6.92
(m, 14H, CHarom),4.42 (s, 2H, CH2aliph), 3.88 (s, 2H,
NH2);13C‐NMR (DMSO‐d6),δ ppm: 190.12, 169.14,
164.12, 149.45, 141.94, 139.14, 137.11, 135.30, 136.24,
135.00, 132.11, 130.09, 129.17, 128.75, 127.11, 125.14,
119.11, 117.41, 116.17, 114.14, 113.17, 63.11; DEPT 135
(300 MHz, DMSO‐d6): 63.11 (CH2) ppm disappeared.
Elemental Analysis: Calcd. C, 69.55; H, 5.35; N, 13.52,
found C, 69.53; H, 5.31; N, 13.50.
ORCID
Antar A. Abdelhamid
https://orcid.org/0000-0002-2814-
7499
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