Simple practical method for synthesis of trisubstituted imidazoles: an efficient copper catalyzed multicomponent reaction

Article abstract of DOI:10.1039/d1ra01767e

A rapid practical process has been developed for synthesis of 2,4,5-trisubstituted-imidazoles in excellent yields up to 95% from readily available starting materials. In this CuI catalyzed synthesis, trisubstituted imidazoles were afforded in short reaction times, wherein the substrate scope is well explored with benzoin as well as benzil reacting with different aldehydes in the presence of ammonium acetate as the nitrogen source.

Full text of DOI:10.1039/d1ra01767e

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Simple practical method for synthesis of
trisubstituted imidazoles: an efficient copper
catalyzed multicomponent reaction†
Cite this: RSC Adv., 2021, 11, 21955
*
Vikas D. Kadu,
Ganesh A. Mali, Siddheshwar P. Khadul and Gokul J. Kothe
A rapid practical process has been developed for synthesis of 2,4,5-trisubstituted-imidazoles in excellent
yields up to 95% from readily available starting materials. In this CuI catalyzed synthesis, trisubstituted
imidazoles were afforded in short reaction times, wherein the substrate scope is well explored with
benzoin as well as benzil reacting with different aldehydes in the presence of ammonium acetate as the
nitrogen source.
Received 5th March 2021
Accepted 16th May 2021
DOI: 10.1039/d1ra01767e
rsc.li/rsc-advances
synthesis of trisubstituted imidazoles.31 But, alternative method
development for regiocontrolled substituted imidazoles has
Introduction
strategic importance due to a few shortcomings such as
complex starting materials, use of strong oxidants, requirement
of stoichiometric amounts of toxic metals, microwave condi-
tions, byproducts formation and tedious work up procedures.
The importance of economic viability and nature balance
means the development of environmentally benign, simple and
fast protocols for synthesis of polysubstituted imidazoles still
has signicant scope. To continue efforts towards synthesis of
nitrogen containing heterocycles,32–36 herein we are going to
report an alternative simple and efficient method for the
synthesis of polysubstituted imidazoles.
The ve-membered aromatic imidazole ring is an important
heterocycle broadly present in various natural products and
synthetic molecules with a broad range of medicinal applica-
tions.1–7 Furthermore, they possess diverse biological properties
such as antibacterial, antifungal, anticancer, anti-
inammatory, antihistaminic, antitubercular, antihyperten-
sive, antiviral, antineuropathic, anti-obesity, antiparasitic and
have possible applications in pathology and diagnostics.6 The
imidazole core is an important aromatic heterocycle which has
broad therapeutic interest due to its two nitrogen atoms leading
to hydrogen bond creation for improving water solubility
properties. Further, the imidazole nucleus has been recognized
as an important isostere of amide, thiazole, tetrazole, pyrazole,
oxazole and triazole with an attractive binding site available for
interacting with various biomolecules, anions and cations in
biological systems offering potential in imidazole-based drug
discovery and developments.8 Furthermore, imidazole has good
photophysical properties,9–17 and is used as a ligand in homo-
geneous catalysis18–20 and functionalized materials.21–30
Several imidazole-based scaffolds have been widely utilized
in the clinic for treatment of different diseases with great
therapeutic potency, which have proved the great development
signicance. Imidazole-based medicinal chemistry research is
rapidly becoming an active area, and chemists are encouraged
by these imidazole-linked drugs as enormous therapeutic
assets. Moreover, it is gaining importance in agrochemicals,
solar cell dyes, and functional materials; the process develop-
ment has good functional group tolerance and substrate exi-
bility is increasing. Several methods have been reported for
Results and discussion
We started by investigating 4-chlorobenzaldehyde 1a (1 mmol),
benzoin 2a (1 mmol) and ammonium acetate 3 (3 mmol) as
model substrates in the presence of (20 mol%) Cu(I) catalysts.
We screened CuCl, CuBr and CuI catalysts; where 75% yield of
the anticipated product 4a was obtained aer 90 min in DMSO
as reaction medium with CuI catalyst at 140 ꢀC (Table 1, entries
1–3). From these results, the reaction was further optimized by
using CuI (20 mol%) with various solvents. Initially, the reaction
ꢀ
was carried out in DMF at 140 C temperature which afforded
desired product 4a in 65% yield (Table 1, entry 4). By consid-
ering green chemistry principles and keeping in mind their
pharmaceutical importance, the reaction conditions were
further optimized using green solvents to nd the best condi-
tions. Gratifyingly, when it was optimized to use butanol solvent
at reux, the product 4a was afforded in 85% yield within
20 min (Table 1, entry 5). Aer that, the reaction was investi-
gated with ethanol solvent at reux; where the anticipated
product 4a was obtained in 76% yield in a slightly greater time
up to 70 min (Table 1, entry 6). Moreover, the reaction studied
School of Chemical Sciences, Punyashlok Ahilyadevi Holkar Solapur University,
Solapur-413255, Maharashtra, India. E-mail: vikaskadu1@gmail.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra01767e
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 21955–21963 | 21955

View Article Online
RSC Advances
Paper
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Solvent
Temp (ꢀC)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMSO
DMSO
DMSO
DMF
BuOH
EtOH
140
140
140
140
reux
reux
reux
reux
110
90 min
90 min
90 min
90 min
20 min
70 min
90 min
90 min
90 min
90 min
90 min
20 min
25 min
30 min
80 min
80 min
90 min
60
65
75
65
85
76
74
10
67
56
68
85
84
83
80
78
64
MeOH
H2O
9
Toluene
Chlorobenzene
CH3CN
BuOH
BuOH
BuOH
BuOH
BuOH
—
10
11
12c
13d
14e
15c
16c
17c
120
reux
reux
reux
reux
90
70
100
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3 (3 mmol), CuI (20 mol%), solvent (7 mL). b Isolated yield. c 15 mol% CuI catalyst was used.
d
10 mol% CuI catalyst was used. e 5 mol% CuI catalyst was used.
with methanol solvent reuxed at 65 ꢀC procured the product 4a
in 74% yield aer 90 min (Table 1, entry 7).
By using the optimized reaction conditions, we explored the
substrate scope for benzoin 2a against various aryl, heteroaryl
In the next step, the reaction was examined with water and aliphatic aldehydes, and the results are depicted in Table 2.
solvent under reuxed conditions; but 4a product formation The different functional groups such as alkyl, halogens, nitro,
was observed only in up to 10% yield with 90 min reaction time methoxy and hydroxyl were found feasible under the optimized
(Table 1, entry 8). Then, the reaction conditions were optimized reaction conditions. The aromatic aldehydes furnished the
ꢀ
with nonpolar solvents such as toluene (at 110 C) and chloro- desired products in good to high yields with both electron-
ꢀ
benzene (at 120 C) which afforded the product 4a in yields of donating and electron-withdrawing groups. The p-substituted
67% and 56% respectively (Table 1, entries 9–10). Furthermore, electron-donating and electron-withdrawing aryl aldehydes
the reaction carried out in CH3CN solvent at reux obtained such as 4-Cl, 4-OMe, 4-OH, 4-CN and 4-NO2 were studied and
a yield of product 4a of up to 68% in 90 min (Table 1, entry 11). afforded the desired products 4a (85%), 4b (94%), 4c (92%), 4e
To nd out the best optimized conditions, the catalyst loading (84%) and 4f (92%) (Table 2). Furthermore, the sterically
was examined, and the same results were reproduced with hindered, o-substituted aryl aldehydes such as 2-F and 2-NO2
15 mol% CuI catalyst (Table 1, entry 12). Further, the reaction furnished products 4g (89%) and 4h (95%) (Table 2, entries 7–
was also studied in the presence of 10 mol% and 5 mol% CuI 8). Then, the m-substituted (3-OMe and 3-NO2) aryl aldehydes
catalyst, which resulted in slightly lower yields of the desired were also explored and provided the preferred products (4i and
product in 25 min and 30 min reaction times respectively (Table 4j) in 92% and 96% yields respectively (Table 2, entries 9–10).
1, entry 13–14). Next, we investigated the temperature effects Aer that, the substrate scope was extended with disubstituted
and the product 4a was obtained in lower yields of 80% and functional groups; where the trisubstituted imidazoles were
78% aer 80 min for 90 ꢀC and 70 ꢀC respectively (Table 1, afforded in excellent yields of 92% (4k; 2-Cl, 4-Cl), 94% (4l; 2-Cl,
entries 15–16). Aer that, the reaction was studied in neat 6-F), 90% (4m; 3-OMe, 4-OH), 92% (4n; 2,5-OMe) and 94% (4o;
reaction conditions; where the anticipated product 4a formed in 3,4-OMe) (Table 2, entries 11–15). In addition, the optimized
up to 64% yield (Table 1, entry 17). Therefore, the reaction conditions were used for 1-naphthaldehyde and heteroaryl
conditions described in entry 12 were noted to be optimal, aldehydes (1H-indole-3-carbaldehyde, picolinaldehyde and
tolerating for maximum conversion to the desired trisubstituted thiophene-2-carbaldehyde) which provided the products in
imidazole product 4a.
21956 | RSC Adv., 2021, 11, 21955–21963
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Table 2 Substrate scope with benzoin for trisubstituted imidazole synthesisa
Entry
1
4
Time (min)
20
Yieldb (%)
Entry
11
4
Time (min)
Yieldb (%)
4a (85%)
40
45
4k (92%)
2
3
20
30
4b (94%)
4c (92%)
12
13
4l (94%)
40
30
4m (90%)
4
35
4d (86%)
14
4n (92%)
5
6
35
40
4e (84%)
4f (92%)
15
16
30
30
4o (94%)
4p (95%)
7
8
45
40
4g (89%)
4h (95%)
17
18
65
60
4q (84%)
4r (83%)
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 21955–21963 | 21957

View Article Online
RSC Advances
Paper
Table 2 (Contd.)
Entry
9
4
Time (min)
Yieldb (%)
Entry
19
4
Time (min)
Yieldb (%)
30
4i (92%)
60
90
4s (88%)
10
45
4j (96%)
20
4t (80%)
a
Reaction conditions: 1 (1 mmol, 1.0 equiv.), 2a (1 mmol, 1.0 equiv.), 3 (3 mmol, 3.0 equiv.), CuI (15 mol%), BuOH (7 mL) at reux. b Isolated yield.
signicant yields: 4p (95%), 4q (84%), 4r (83%) and 4s (88%) converted into E by loss of water which further converts into
(Table 2, entries 16–19).
intermediate F via oxidation in the presence of CuI catalyst.43–48
Further, the utility of the present method was investigated The same F intermediate formation takes place from interme-
with aliphatic heptanal aldehyde, where the product 4t was diate D by loss of water. At the end, the desired product 4a
obtained in 80% yield (Table 2, entry 20). With the same opti- formation takes place from common intermediate F via [1,5]-H-
mized conditions, the applicability of the developed system was transfer.49
evaluated using benzil 2b which reacted in the same fashion
with different substituted aldehydes and afforded trisubstituted
imidazoles in high yields as summarized in Table 3. Various
Conclusion
toxic oxidant catalysed reactions are used to synthesise 1,2-
In conclusion, we have developed a practical method for
synthesis of 2,4,5-trisubstituted imidazoles. The present
method has a great advantage of substrate scope with a-hydroxy
ketone (benzoin) as well as 1,2-diketone (benzil). This three
component reaction is effective due to good yields in a short
time and simple reaction conditions.
diketones such as benzil from a-hydroxy ketone (benzoin).37–39
Numerous reports of the synthesis of trisubstituted imidazoles
using 1,2-diketones have been reported but not from a-hydroxy
ketone. Herein, our developed method for the synthesis of
trisubstituted imidazoles from a-hydroxy ketone (benzoin) as
well as 1,2-diketones (benzil) has great utility.
The plausible mechanism for the trisubstituted imidazole
synthesis is summarized in Scheme 1. From the relevant liter-
ature and experimental results, different pathways have been
proposed for benzil and benzoin as starting materials.40–45
Experimental section
General information
All solvents used in the reactions were distilled for purity. The
reagents were commercially available and used directly without
purication unless otherwise stated. Melting points were
recorded with a Thomas-Hoover capillary melting point appa-
ratus. The thin layer chromatography (TLC) was performed
using silica gel plates (GF254) with 100–120 mesh size and
visualization was effected with a short-wavelength UV lamp (254
Initially, the condensation of 4-chlorobenzaldehyde with
ammonia produced from ammonium acetate generates inter-
mediate A.42,44 Simultaneously, benzoin 2a reacts with ammo-
nium acetate and leads to the formation of intermediate I which
further converts into II via tautomerism. Aerwards, the formed
intermediates I and II react with intermediate A which converts
into intermediate C.44 On the other hand, the intermediate A
gets converted into (4-chlorophenyl)methanediamine B by
reacting with another ammonia molecule. Then, the interme-
diate B reacts with benzoin 2a and benzil 2b to afford inter-
mediates C and D respectively. Aer that, intermediate C gets
1
nm). H and 13C NMR spectra were recorded using Jeol as well
as Bruker NMR instruments at 400 and 100 MHz using DMSO
and CDCl3 solvents. The chemical shis are expressed in d,
parts per million (ppm) with reference to internal standard
TMS. The spin multiplicities are represented by the symbols s
21958 | RSC Adv., 2021, 11, 21955–21963
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Table 3 Substrate scope with benzil for trisubstituted imidazole synthesisa
Entry
1
4
Time (min)
45
Yieldb (%)
Entry
11
4
Time (min)
Yieldb (%)
4a (84%)
60
55
4k (91%)
2
3
45
50
4b (92%)
4c (91%)
12
13
4l (92%)
50
45
4m (88%)
4
50
4d (85%)
14
4n (90%)
5
6
50
55
4e (82%)
4f (91%)
15
16
45
45
4o (93%)
4p (94%)
7
60
4g (88%)
17
80
4q (83%)
8
9
60
50
4h (94%)
4i (90%)
18
19
80
80
4r (81%)
4s (87%)
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 21955–21963 | 21959

View Article Online
RSC Advances
Paper
Table 3 (Contd.)
Entry
4
Time (min)
Yieldb (%)
Entry
4
Time (min)
Yieldb (%)
10
60
4j (94%)
20
90
4t (79%)
a
Reaction conditions: 1 (1 mmol, 1.0 equiv.), 2b (1 mmol, 1.0 equiv.), 3 (3 mmol, 3.0 equiv.), CuI (15 mol%), BuOH (7 mL) at reux. b Isolated yield.
(singlet), d (doublet), t (triplet), q (quartet), p (pentet), and m DMSO-d6) d 9.73 (s, 1H), 7.87 (d, J ¼ 8.6 Hz, 2H), 7.48 (d, J ¼
(multiplet) and coupling constants (J) are reported in hertz (Hz). 7.3 Hz, 4H), 7.19–7.36 (6H), 6.83 (d, J ¼ 8.6 Hz, 2H), 3.41 (s,
1H) ppm; 13C NMR (100 MHz, DMSO-d6) d 158.4, 146.6, 134.0,
133.8, 129.6, 129.3, 128.9, 128.7, 128.2, 127.5, 127.4, 127.0,
126.7, 122.0, 116.0 ppm.
General procedure for synthesis of imidazoles (4)
In a round bottom ask, the mixture of aldehyde 1 (1 mmol),
2,4,5-Triphenyl-1H-imidazole (4d). White solid; mp: 276–
278 ꢀC [Lit.50 275–277 ꢀC]; 1H NMR (400 MHz, CDCl3) d 9.26 (s,
benzoin 2a or benzil 2b (1 mmol), NH4OAc (3 mmol), CuI
(15 mol%) and BuOH (7 mL) was reuxed. The progress of the
1H, NH), 7.94–7.91 (m, 2H), 7.63–7.45 (m, 6H), 7.42–7.01 (m,
reaction was monitored using thin layer chromatography (TLC)
7H) ppm.
technique. Aer completion of the reaction, the mixture was
4-(4,5-Diphenyl-1H-imidazol-2-yl)benzonitrile (4e). White
solid; mp: 186–187 ꢀC [Lit.50 185 ꢀC]; 1H NMR (400 MHz, DMSO-
cooled to room temperature and poured into crushed ice. The
precipitated solid product was stirred at room temperature and
d6) d 12.99 (s, 1H), 8.21–7.90 (m, 4H), 7.49–7.27 (m, 10H) ppm;
13C NMR (100 MHz, DMSO-d6) d 144.2, 138.6, 135.2, 134.8,
ltered to obtain sufficient pure crude product 4. The product
was recrystallized by using ethanol solvent.
133.3, 131.1, 130.1, 129.3, 129.1, 128.8, 127.6, 127.4, 126.0,
119.5, 110.6 ppm.
2-(4-Nitrophenyl)-4,5-diphenyl-1H-imidazole (4f). Orange
Characterization data of pure polysubstituted imidazole
products
1
solid; mp: 242–244 C [Lit.51 230–232 C]; H NMR (400 MHz,
DMSO-d6) d 13.12 (s, 1H), 8.35–8.25 (m, 4H), 7.62–7.35 (m, 8H),
7.30–7.20 (m, 2H) ppm; 13C NMR (100 MHz, DMSO-d6) d 147.0,
143.9, 139.0, 136.6, 135.1, 131.0, 130.6, 129.6, 129.3, 129.1,
128.8, 127.7, 127.5, 126.3, 124.8 ppm.
ꢀ
ꢀ
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (4a). White
1
solid; mp: 260–262 C [Lit.50 260–262 C]; H NMR (400 MHz,
DMSO-d6) d 12.87 (s, 1H), 8.06 (dt, J ¼ 9.2 and 2.3 Hz, 2H), 7.53–
7.32 (m, 9H), 7.28–7.17 (m, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6) d 144.9, 137.8, 135.5, 133.3, 131.4, 129.7, 129.3, 129.2,
129.1, 129.0, 128.8, 128.4, 127.6, 127.4, 127.2 ppm.
ꢀ
ꢀ
2-(2-Fluorophenyl)-4,5-diphenyl-1H-imidazole (4g). White
1
solid; mp: 257–259 C [Lit.50 188–189 C]; H NMR (400 MHz,
DMSO-d6) d 12.53 (s, 1H), 7.96 (t, J ¼ 7.0 Hz, 1H), 7.51–7.25 (m,
12H), 7.19 (t, J ¼ 7.3 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-
d6) d 160.6, 158.1, 141.4, 137.7, 135.5, 131.4, 131.0, 130.9, 130.2,
129.2, 129.1, 128.7, 128.4, 127.7, 127.1, 125.2, 119.3, 119.1,
116.9, 116.7 ppm.
ꢀ
ꢀ
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (4b). White
1
solid; mp: 228–230 C [Lit.50 227–229 C]; H NMR (400 MHz,
DMSO-d6) d 12.48 (s, 1H), 7.98 (d, J ¼ 9.2 Hz, 2H), 7.51–7.38 (m,
6H), 7.34–7.15 (m, 4H), 7.00 (d, J ¼ 9.2 Hz, 2H), 3.77 (s, 3H) ppm;
13C NMR (100 MHz, DMSO-d6) d 159.9, 146.1, 137.3, 135.8,
131.7, 129.2, 128.9, 128.7, 128.2, 127.6, 127.2, 126.9, 123.6,
114.6, 55.7 ppm.
ꢀ
ꢀ
2-(2-Nitrophenyl)-4,5-diphenyl-1H-imidazole (4h). Yellow
1
solid; mp: 246–250 C [Lit.52 247–249 C]; H NMR (400 MHz,
DMSO-d6) d 12.95 (s, 1H), 7.96 (d, J ¼ 7.9 Hz, 1H), 7.89 (d, J ¼
7.9 Hz, 1H), 7.75 (t, J ¼ 7.6 Hz, 1H), 7.65–7.58 (m, 1H), 7.48–7.33
ꢀ
ꢀ
2-(4-Hydroxyphenyl)-4,5-diphenyl-1H-imidazole (4c). White
1
solid; mp: 269–271 C [Lit.50 270–272 C]; H NMR (400 MHz,
ꢀ
ꢀ
21960 | RSC Adv., 2021, 11, 21955–21963
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Scheme 1 Plausible reaction mechanism.
(m, 7H), 7.27 (t, J ¼ 7.3 Hz, 2H), 7.19 (t, J ¼ 7.3 Hz, 1H) ppm; 13
C
7.59 (dd, J ¼ 8.6, 2.4 Hz, 1H), 7.51–7.17 (m, 11H) ppm; 13C NMR
NMR (100 MHz, DMSO-d6) d 148.9, 141.6, 138.1, 135.2, 132.7, (100 MHz, DMSO-d6) d 143.1, 137.4, 135.5, 133.7, 133.6, 131.4,
131.2, 130.3, 130.1, 129.3, 129.3, 128.8, 128.6, 127.5, 127.3, 129.2, 128.8, 128.7, 128.6, 128.3, 127.7, 127.1, 118.1, 117.9,
124.6, 123.9 ppm.
115.3, 115.1 ppm.
2-(3-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (4i). White
2-(2-Chloro-6-uorophenyl)-4,5-diphenyl-1H-imidazole (4l).
1
1
solid; mp: 290–295 C [Lit.53 266–268 C]; H NMR (400 MHz, White solid; mp: 203–205 C [Lit.55 204–206 C]; H NMR (400
DMSO-d6) d 12.66 (s, 1H), 7.65–7.62 (m, 2H), 7.52–7.33 (m, 8H), MHz, DMSO-d6) d 12.86 (s, 1H), 7.65–7.46 (m, 6H), 7.40–7.22 (m,
7.27 (t, J ¼ 7.6 Hz, 2H), 7.18 (t, J ¼ 7.0 Hz, 1H), 6.91 (dd, J ¼ 7.6, 7H) ppm; 13C NMR (100 MHz, DMSO-d6) d 162.6, 160.1, 137.9,
2.1 Hz, 1H), 3.79 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) 135.2, 135.1, 132.5, 132.4, 129.3, 128.8, 128.4, 127.7, 126.3,
d 160.1, 145.9, 137.6, 135.6, 132.1, 131.6, 130.4, 129.2, 129.0, 126.3, 120.3, 120.1, 115.5, 115.2 ppm.
ꢀ
ꢀ
ꢀ
ꢀ
128.8, 128.7, 128.4, 127.6, 127.1, 118.1, 114.8, 110.7, 55.7 ppm.
4-(4,5-Diphenyl-1H-imidazol-2-yl)-2-methoxyphenol
(4m).
2-(3-Nitrophenyl)-4,5-diphenyl-1H-imidazole (4j). Yellow Off white solid; mp: 259–261 ꢀC [Lit.50 260 ꢀC]; 1H NMR (400
solid; mp: 226–228 ꢀC [Lit.50 230 ꢀC]; 1H NMR (400 MHz, CDCl3) MHz, DMSO-d6) d 12.40 (s, 1H), 9.26 (s, 1H), 7.60 (d, J ¼ 1.8 Hz,
d 12.49 (s, 1H, NH), 9.02 (s, 1H), 8.53 (d, J ¼ 7.2 Hz, 1H), 8.11 (d, 1H), 7.51–7.30 (m, 8H), 7.34–7.15 (m, 3H), 6.82 (d, J ¼ 7.9 Hz,
J ¼ 6.4 Hz, 1H), 7.61–7.51 (m, 6H), 7.35–7.19 (m, 5H) ppm.
1H), 3.82 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) d 148.2,
2-(2,4-Dichlorophenyl)-4,5-diphenyl-1H-imidazole
(4k). 147.5, 146.6, 137.1, 135.9, 131.9, 129.2, 128.9, 128.7, 128.1,
1
White solid; mp: 174–176 C [Lit.54 174–175 C]; H NMR (400 127.9, 127.5, 126.9, 122.4, 118.8, 116.1, 109.8, 56.2 ppm.
ꢀ
ꢀ
MHz, DMSO-d6) d 12.64 (s, 1H), 7.81 (dd, J ¼ 8.9, 6.4 Hz, 1H),
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 21955–21963 | 21961

View Article Online
RSC Advances
Paper
3 S. N. Riduan and Y. Zhang, Chem. Soc. Rev., 2013, 42, 9055–
9070.
4 N. Rani, A. Sharma, G. K. Gupta and R. Singh, Mini-Rev. Med.
Chem., 2013, 13, 1626–1655.
5 M. V. Castelli, E. Butassi, M. C. Monteiro, L. A. Svetaz,
F. Vicente and S. A. Zacchino, Expert Opin. Ther. Pat., 2014,
24, 323–338.
2-(2,5-Dimethoxyphenyl)-4,5-diphenyl-1H-imidazole
(4n).
1
White solid; mp: 180–182 C [Lit.56 185–186 C]; H NMR (400
MHz, CDCl3) d 10.6 (s, 1H, NH), 8.03 (d, J ¼ 3.2 Hz, 1H), 7.69–
6.95 (m, 10H), 6.96 (d, J ¼ 8.8 Hz, 1H), 6.89 (dd, J ¼ 9.2 & 3.2 Hz,
1H), 3.99 (s, 3H, OMe), 3.89 (s, 3H. OMe) ppm; 13C NMR (100
MHz, CDCl3) d 154.3, 150.2, 144.0, 128.9, 128.3, 127.8, 116.2,
112.7, 112.1, 56.4, 56.0 ppm.
ꢀ
ꢀ
6 L. Zhang, X. M. Peng, G. L. V. Damu, R. X. Geng and
C. H. Zhou, Med. Res. Rev., 2014, 34, 340–437.
7 N. A. Bhowmick, A. Chytil, D. Plieth, A. E. Gorska,
N. Dumont, S. Shappell, M. K. Washington, E. G. Neilson
and H. L. Moses, Science, 2004, 303, 848–851.
8 P. N. Chopra and J. K. Sahu, Curr. Drug Discovery Technol.,
2020, 17, 574–584.
9 S. Somasundaram, E. Kamaraj, S. J. Hwang, S. Jung,
M. G. Choi and S. Park, J. Mol. Struct., 2017, 1137, 43–49.
10 Y. He, Y. Huang, J. Li, X. Pang and G. Yang, Org. Electron.,
2017, 50, 220–227.
11 B. Rajamouli, R. Devi, A. Mohanty, V. Krishnan and
S. Vaidyanathan, New J. Chem., 2017, 41, 9826–9839.
12 L. He, Z. Wang, C. Yang, L. Duan, R. Tang, X. Song and
C. Pan, Dyes Pigm., 2016, 131, 76–83.
13 S. Das, S. Karmakar, D. Saha and S. Baitalik, Inorg. Chem.,
2013, 52, 6860–6879.
2-(3,4-Dimethoxyphenyl)-4,5-diphenyl-1H-imidazole
(4o).
White solid; mp: 218–220 ꢀC [Lit.50 220 ꢀC]; 1H NMR (400 MHz,
CDCl3) d 7.58–7.47 (m, 5H), 7.37–7.24 (m, 8H), 6.90 (d, J ¼
7.2 Hz, 1H), 3.92 (s, 3H, OMe), 3.91 (s, 3H, OMe) ppm; 13C NMR
(100 MHz, CDCl3) d 149.8, 149.4, 146.1, 127.8, 127.4, 123.1,
117.4, 111.1, 109.0, 56.0, 55.9 ppm.
2-(Naphthalen-1-yl)-4,5-diphenyl-1H-imidazole (4p). White
1
solid; mp: 263–265 C [Lit.57 262–263 C]; H NMR (400 MHz,
DMSO-d6) d 12.77 (s, 1H), 9.15 (d, J ¼ 8.6 Hz, 1H), 7.97 (d, J ¼
7.9 Hz, 2H), 7.93 (d, J ¼ 6.7 Hz, 1H), 7.61–7.52 (m, 7H), 7.43–7.20
(m, 6H) ppm; 13C NMR (100 MHz, DMSO-d6) d 146.1, 137.6,
135.8, 134.2, 131.5, 130.8, 129.5, 129.2, 128.9, 128.8, 128.5,
128.3, 127.9, 127.7, 127.3, 127.1, 126.7, 125.8 ppm.
ꢀ
ꢀ
3-(4,5-Diphenyl-1H-imidazol-2-yl)-1H-indole (4q). Off white
1
solid; mp: 307–308 C [Lit.58 308–310 C]; H NMR (400 MHz,
DMSO-d6) d 12.25 (s, 1H), 11.34 (d, J ¼ 1.8 Hz, 1H), 8.44 (d, J ¼
7.3 Hz, 1H), 8.18–7.96 (m, 1H), 7.67–7.54 (m, 2H), 7.49–7.26 (m,
8H), 7.19–7.09 (m, 3H) ppm; 13C NMR (100 MHz, DMSO-d6)
d 144.2, 136.8, 136.5, 136.2, 132.1, 129.2, 128.7, 127.9, 127.4,
126.7, 126.3, 125.6, 124.3, 122.4, 122.0, 120.2, 112.1, 107.3 ppm.
ꢀ
ꢀ
14 D. Ray, A. Pramanik and N. Guchhait, J. Photochem.
Photobiol., A, 2015, 302, 42–50.
´
´
15 A. Baez-Castro, J. Baldenebro-Lopez, D. Glossman-Mitnik,
¨
´
H. Hop, A. Cruz-Enrıquez, V. Miranda-Soto, M. Parra-
Hake and J. J. Campos-Gaxiola, J. Mol. Struct., 2015, 1099,
126–134.
2-(4,5-Diphenyl-1H-imidazol-2-yl)pyridine (4r). Greenish
1
yellow solid; mp: 173–175 C [Lit.59 174–176 C]; H NMR (400
MHz, DMSO-d6) d 13.15 (s, 1H), 8.60 (s, 1H), 8.12–7.87 (m, 2H),
7.64–7.46 (m, 5H), 7.35–7.19 (m, 6H) ppm; 13C NMR (100 MHz,
DMSO-d6) d 149.5, 149.3, 146.0, 138.4, 137.8, 135.6, 131.2, 129.8,
129.1, 129.0, 128.7, 128.3, 127.9, 127.2, 123.7, 120.4 ppm.
ꢀ
ꢀ
16 D. Ray, A. Pramanik and N. Guchhait, J. Photochem.
Photobiol., A, 2014, 274, 33–42.
17 D. Ray, A. Pramanik and N. Guchhait, RSC Adv., 2014, 4,
13256–13265.
18 R. J. Bernot, M. A. Brueseke, M. A. Evans-White and
G. A. Lamberti, Environ. Toxicol. Chem., 2005, 24, 87–92.
19 Y. Cao, R. Zhang, T. Cheng, J. Guo, M. Xian and H. Liu, Appl.
Microbiol. Biotechnol., 2017, 101, 521–532.
20 Y. Qiang, S. Zhang, L. Guo, X. Zheng, B. Xiang and S. Chen,
Corros. Sci., 2017, 119, 68–78.
4,5-Diphenyl-2-(thiophen-2-yl)-1H-imidazoꢀle (4s). Faint
1
yellow solid; mp: 262–264 C [Lit.55 259–261 C]; H NMR (400
ꢀ
MHz, DMSO-d6) d 12.77 (s, 1H), 7.66 (d, J ¼ 3.1 Hz, 1H), 7.52–
7.31 (m, 8H), 7.26 (t, J ¼ 7.6 Hz, 2H), 7.20–7.10 (m, 2H) ppm; 13
C
NMR (100 MHz, DMSO-d6) d 142.1, 137.3, 135.3, 134.5, 131.4,
129.3, 128.8, 128.8, 128.5, 128.4, 128.2, 127.6, 127.1, 126.8,
124.8 ppm.
21 X. Meng, H.-N. Wang, S.-Y. Song and H.-J. Zhang, Chem. Soc.
Rev., 2017, 46, 464–480.
2-Hexyl-4,5-diphenyl-1H-imidazole (4t). Faint yellow solid;
1
mp: 130–132 ꢀC [Lit.54 129–130 ꢀC]; H NMR (400 MHz, DMSO-
22 C. Li, J. Tan, J. Gu, Y. Xue, L. Qiao and Q. Zhang, Compos. Sci.
Technol., 2017, 142, 198–206.
23 M. Schuster, T. Rager, A. Noda, K. D. Kreuer and J. Maier,
Fuel Cells, 2005, 5, 355–365.
24 S. Park, O.-H. Kwon, S. Kim, S. Park, M.-G. Choi, M. Cha,
S. Y. Park and D.-J. Jang, J. Am. Chem. Soc., 2005, 127,
10070–10074.
d6) d 12.07 (s, 1H), 7.39 (d, J ¼ 6.7 Hz, 4H), 7.27 (t, J ¼ 7.6 Hz,
4H), 7.19 (t, J ¼ 7.3 Hz, 2H), 2.60 (t, J ¼ 7.9 Hz, 2H), 1.70–1.63 (m,
2H), 1.33–1.25 (m, 6H), 0.83 (t, J ¼ 7.0 Hz, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6) d 148.9, 134.3, 134.1, 133.9, 128.9, 128.6,
128.4, 128.1, 127.8, 127.5, 127.2, 31.5, 29.0, 28.6, 28.4, 22.6,
14.5 ppm.
25 M. F. H. Schuster, W. H. Meyer, M. Schuster and
K. D. Kreuer, Chem. Mater., 2004, 16, 329–337.
26 K. D. Kreuer, J. Membr. Sci., 2001, 185, 29–39.
27 E. B. Anderson and T. E. Long, Polymer, 2010, 51, 2447–2454.
28 B. Li, R. Wen, S. Xue, L. Shi, Z. Tang and Z. Wang, Mater.
Chem., 2017, 1, 646–653.
Conflicts of interest
There are no conicts of interest to declare.
References
1 M. Gaba and C. Mohan, Med. Chem. Res., 2016, 25, 173–210.
2 L. De Luca, Curr. Med. Chem., 2006, 13, 1–23.
21962 | RSC Adv., 2021, 11, 21955–21963
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
29 Z. Song, W. Zhang, M. Jiang, H. H. Y. Sung, R. T. K. Kwok, 44 S. A. Siddiqui, U. C. Narkhede, S. S. Palimkar, T. Daniel,
H. Nie, I. D. Williams, B. Liu and B. Z. Tang, Adv. Funct.
Mater., 2016, 26, 824–832.
R. J. Lahoti and K. V. Srinivasan, Tetrahedron, 2005, 61,
3539–3546.
30 F. M. Zhang, L. Z. Dong, J. S. Qin, W. Guan, J. Liu, S. L. Li, 45 M. Bakavoli, H. Eshghi, A. Mohammadi, H. Moradi and
M. Lu, Y. Q. Lan, Z. M. Su and H. C. Zhou, J. Am. Chem.
Soc., 2017, 139, 6183–6189.
31 D. A. Shabalin and J. E. Camp, Org. Biomol. Chem., 2020, 18,
3950–3964.
32 V. D. Kadu, S. N. Chandrudu, M. G. Hublikar, D. G. Raut and
R. B. Bhosale, RSC Adv., 2020, 10, 23254–23262.
33 M. Hublikar, V. Kadu, J. K. Dublad, D. Raut, S. Shirame,
J. Ebrahimi, Iran. J. Catal., 2015, 5, 237–243.
46 M. Largeron and M.-B. Fleury, Angew. Chem., 2012, 124,
5505–5508.
47 R. D. Patil and S. Adimurthy, Adv. Synth. Catal., 2011, 353,
1695–1700.
48 J. Liu, C. Wang, X. Ma, X. Shi, X. Wang, H. Li and Q. Xu,
Catal. Lett., 2016, 146, 2139–2148.
P. Makam and R. Bhosale, Arch. Pharm., 2020, 353, 2000003. 49 N. D. Kokare, J. N. Sangshetti and D. B. Shinde, Synthesis,
34 V. D. Kadu, M. G. Hublikar, D. G. Raut and R. B. Bhosale,
Asian J. Chem., 2019, 31, 1189–1194.
35 D. G. Raut, S. B. Patil, V. D. Kadu, M. G. Hublikar and
2007, 2007, 2829–2834.
50 K. S. Niralwad, B. B. Shingate and M. S. Shingare, J.
Heterocycl. Chem., 2011, 48, 742–745.
R. B. Bhosale, Anti-Cancer Agents Med. Chem., 2018, 18, 51 S. A. Dake, M. B. Khedkar, G. S. Irmale, S. J. Ukalgaonkar,
2117–2123.
V. V. Thorat, S. A. Shintre and R. P. Pawar, Synth.
Commun., 2012, 42, 1509–1520.
52 A. Puratchikody and M. Doble, Chem. Biol. Drug Des., 2009,
74, 173–182.
53 R. Bansal, P. K. Soni and A. K. Halve, J. Heterocycl. Chem.,
2018, 55, 1308–1312.
36 V. D. Kadu, D. N. Nadimetla, M. G. Hublikar, D. G. Raut and
R. B. Bhosale, Lett. Org. Chem., 2020, 17, 61–67.
37 A. McKillop, B. P. Swann, M. E. Ford and E. C. Taylor, J. Am.
Chem. Soc., 1973, 95, 3641–3645.
¨
38 J. Heinze, H. Baumgartel and H. Zimmermann, Chem. Ber.,
1968, 101, 3504–3516.
54 F. Xu, N. Wang, Y. Tian and G. Li, J. Heterocycl. Chem., 2013,
50, 668–675.
55 A. Dandia, V. Parewa, A. Sharma and K. S. Rathore, Eur.
Chem. Bull., 2013, 2, 971–974.
56 H. Goudarziafshar, A. R. Moosavi-Zare and Z. Jalilian, Org.
Chem. Res., 2020, 6, 69–81.
57 B. Somashekara, B. Thippeswamy and G. R. Vijayakumar, J.
Chem. Sci., 2019, 131, 1–7.
58 J. Banothu, R. Gali, R. Velpula and R. Bavantula, Arabian J.
Chem., 2017, 10, S2754–S2761.
59 A. O. Eseola, M. Zhang, J. F. Xiang, W. Zuo, Y. Li,
J. A. O. Woods and W. H. Sun, Inorg. Chim. Acta, 2010, 363,
1970–1978.
39 J. D. Lou, L. Li, N. Vatanian, X. L. Lu and X. Yu, Synth. React.
Inorg., Met.-Org., Nano-Met. Chem., 2008, 38, 373–375.
40 D. Davidson, M. Weiss and M. Jelling, J. Org. Chem., 1937, 2,
328–334.
41 D. Davidson, M. Weiss and M. Jelling, J. Org. Chem., 1937, 2,
319–327.
42 L. M. Wang, Y. H. Wang, H. Tian, Y. F. Yao, J. H. Shao and
B. Liu, J. Fluorine Chem., 2006, 127, 1570–1573.
43 M. V. Marques, M. M. Ruthner, L. A. M. Fontoura and
D. Russowsky, J. Braz. Chem. Soc., 2012, 23, 171–179.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 21955–21963 | 21963