One-Pot Synthesis of 2,4,5-Triphenyl Imidazoles from 1,2-Diols as Key Reagents

Article abstract of DOI:10.1002/jccs.201600746

A simple one-pot procedure for the preparation of 2,4,5-triphenyl imidazole derivatives is presented. The procedure involves the lead tetraacetate oxidation of 1,2-diols to give aldehydes in situ, which then undergo a three-component reaction with benzil and ammonium acetate to yield the imidazole derivatives.

Full text of DOI:10.1002/jccs.201600746

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
One-Pot Synthesis of 2,4,5-Triphenyl Imidazoles from 1,2-Diols as Key Reagents
*
Narasashetty Jagadishbabu and Kalegowda Shivashankar
P. G. Department of Chemistry, Central College Campus, Bangalore University, Bangalore 560 001, India
(Received: September 16, 2016; Accepted: February 2, 2017; DOI: 10.1002/jccs.201600746)
A simple one-pot procedure for the preparation of 2,4,5-triphenyl imidazole derivatives is pre-
sented. The procedure involves the lead tetraacetate oxidation of 1,2-diols to give aldehydes in situ,
which then undergo a three-component reaction with benzil and ammonium acetate to yield the
imidazole derivatives.
Keywords: Imidazoles; Lead tetraacetate; Multicomponent reaction; 1,2-Diols; Benzil;
Ammonium acetate.
INTRODUCTION
Multicomponent reactions (MCRs) have emerged
aldehydes with benzoin or benzil and ammonium
acetate,23 (2) one-pot cyclocondensation of aldehydes
with benzil, aromatic amine, and ammonium acetate,24
and (3) one-pot cyclocondensation of aromatic
nitriles.25 This has led to the development of new,
improved methodologies involving the use of a number
of catalysts such as Yb(OPf )3,26 Cu(NO3)2/zeolite,27
potassium dihydrogen phosphate,28 ZrOCl2.8H2O,29
Zr(acac)4,30 NiCl2.6H2O,31 p-toluenesulfonic acid
(PTSA),32 TiCl4-SiO2,33 MCM-41,34 ZrCl4,35 sodium
bisulfite,36 polymer-supported zinc chloride,37 alum,38
zinc oxide,39 trichloroisocyanuric acid,40 tetrabutyl
ammonium bromide,41 ceric ammonium nitrate,42 nano
copper/cobalt ferrites,43 microwave,44 amberlyst,45
novel polymers,46 antimony trichloride/stannous chlo-
ride dihydrate,47 SbCl3/SiO2,48 sulfamic acid/Fe3O4,49
and nano aluminum nitride.50 Although several meth-
odologies have been documented, most of them have
their own drawbacks such as poor yields, the use of
toxic catalysts, and tedious work-up. Aldehydes are
ubiquitous substrates in many powerful MCRs. How-
ever, they are in general unstable, especially because of
aerial oxidation to acids, and are prone to polymeriza-
tion or hydrolysis. Thus, in many cases aldehydes must
be purified just before their use because the presence of
other products not only affects the concentration of the
active aldehyde but also interferes with the chemical
reactions.51 Hence, there is a need to develop a rapid
and efficient synthetic protocol for the one-pot synthesis
of substituted imidazole scaffolds.
as a powerful tool for industrial and academic research
groups because of their shorter reaction times as well as
the avoidance of the isolation of intermediates, their
purification, and characterization.1–3 Imidazoles have a
privileged structure as they occur as fragments in drugs
displaying
a
wide spectrum of pharmacological
activities.4–9 A large number of compounds bearing
substituted imidazole derivatives have entered preclini-
cal and clinical trials over the last few years. These deri-
vatives represent an important structural motif in
commercial drugs10 such as the anti-gastroesophageal
reflux drug Omeprazole, platelet aggregation inhibitor
Trifenagrel, angiotensin II receptor blocker Olmesartan,
and the anti-high-blood-pressure drugs Eprosartan and
Losartan (Figure 1).
Imidazole derivatives have received significant
importance because of their diverse biological properties
such as anti-inflammatory,11 antimicrobial,12 anticancer,13
antitubercular,14 antifungal,15 antibacterial,16 antiviral,17
antioxidant,18 and amebicidal activities.19 The great
potential of substituted imidazole derivatives in the phar-
maceuticals field has therefore triggered growing interest
in their synthetic study.
These applications have stimulated widespread
interest in the synthesis of imidazole derivatives. The
typical syntheses of imidazole derivatives have been
well documented in the literature.20–22 The most impor-
tant of these are (1) one-pot cyclocondensation of
*Corresponding author. Email: shivashankark@gmail.com
J. Chin. Chem. Soc. 2017
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1

Article
Jagadishbabu and Shivashankar
OH
O
Table 1. Optimization of solvents for the synthesis (4a)
N
N
N
N
N
O
S
N
N
NH
N
RO
Entry
Solvents
Time (h)
Yield (%)
N
H
N
H
O
O
NMe2
Cl
O
1
2
3
4
5
6
7
8
9
DCM
5.5
4.5
3
3
4.5
4
3.5
5.5
5.5
48
71
90
96
74
76
84
45
52
Trifenagrel
Omeprazole
Olmesartan
Dioxane
Acetonitrile
Ethanol
Acetone
THF
Methanol
DMF
DMSO
N
N
N
N
N
N
NH
S
N
HO
HOOC
COOH
Eprosartan
Losartan
Fig. 1. Typical imidazole drugs.
In continuation of our work on the synthesis of
heterocycles and development of useful synthetic
methodologies,2,52–57 in this study we report the use of
lead tetraacetate as an oxidizing agent for the synthesis
of 2,4,5-triphenyl imidazole derivatives under mild con-
ditions. Lead tetraacetate is an inexpensive, commer-
cially available, and easy-to-handle reagent.
same reaction. Among the solvents, ethanol was found to
be the best one for this reaction in terms of yield and
reaction time.
The scope and limitations of this three-component
reaction under optimized reaction conditions were stud-
ied using a variety of 1,2-diols, benzil, and ammonium
acetate. The reaction worked well in case of 1,2-diols
tethered with OH, Cl, Br, F, and OCH3 groups. Mod-
erate yield was obtained for the reaction involving 1,2-
diol tethered with NO2 group. In all cases, the reaction
proceeded smoothly to afford the desired products with
good to excellent yields (Table 2).
Mechanistically,60,61 lead tetraacetate oxidizes 1,2-
diol to benzaldehyde giving acetic acid, which facilitates
the formation of the imine between benzaldehyde and
ammonium acetate. The imine then reacts with the
intermediate that is formed by the reaction of benzil
with ammonium acetate to give the corresponding imid-
azole via cyclization and dehydration (Figure 2).
RESULTS AND DISCUSSION
In our preliminary studies, 1 equiv of 1,2-diphe-
nyl-1,2-ethanediol 1a, 2 equiv of benzil 2, 4 equiv of
ammonium acetate 3, and 1 equiv of lead tetraacetate
in dioxane were chosen for the model reaction
(Scheme 1). Initially, when the model reaction was
carried without lead tetraacetate from room tempera-
ture to 101ꢀC, no desirable product was observed even
after prolonged reaction time. This indicated that an oxi-
dizing agent was absolutely necessary for the reaction.
Interestingly, in the presence of lead tetraacetate, when
the same set of substrates were tested under reflux condi-
tion in dioxane, they provided 4a in 71% yield in 4.5 h.
1
The compound 4a was confirmed by IR and H NMR.
EXPERIMENTAL
From this encouraging result, we were prompted to check
whether the yield could be further improved by changing
the solvent. Other solvents such as DCM, acetonitrile,
ethanol, acetone, THF, methanol, DMF, and DMSO
were screened (Table 1) under reflux condition for the
General information
Melting points were determined on an electric
melting point apparatus and were uncorrected. Fourier
transform infrared (FT-IR) spectra were recorded on
1
an Agilent Cary 630 instrument. H NMR (400 MHz)
O
Pb(OAc)4 / Dry EtOH/ Reflux
N
OH
2
4NH4OAc
+
N
H
2
+
O
2
OH
1a
Pb(OAc)2 +
6AcOH
6H2O +
3
4a
Scheme 1 Synthesis of 2,4,5-triphenyl imidazole derivatives using lead tetraacetate as a reagent.
2
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One-Pot Synthesis of Imidazoles
Table 2. Synthesis of 2,4,5-triphenyl imidazole derivatives (4a–o)
Entry
1
1,2-Diols
Products
Time (h)
3
Yield (%)
96
Obs. Mp (ꢀC)
Lit. Mp (ꢀC)ref
276–278
275–27743
OH
N
OH
N
H
1a
4a
2
2.5
89
233–235
234–23639
Cl
OH
OH
N
Cl
N
H
Cl
Cl
4b
1b
3
4
5
2.5
90
91
92
244–246
218–220
231–233
245–24738
218–22058
OH
Cl
N
Cl
OH
N
H
1c
4c
3
OEt
OH
N
OEt
N
H
OH
EtO
4d
1d
3.5
O
Br
OH
N
Br
O
Br
O
N
H
OH
1e
4e
6
7
4.5
4
82
89
242–244
255–257
240–24223
NO2
OH
N
NO2
N
H
OH
O2N
4f
1f
Br
Br
Cl
N
OH
Cl
N
H
OH
1g
4g
Cl
Br
8
9
3
92
91
232–234
246–248
233–23539
248–25039
OH
N
OH
N
H
1h
4h
3.5
Br
OH
N
Br
OH
N
H
Br
1i
4i
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Article
Jagadishbabu and Shivashankar
Table 2. Continued
Entry
10
1,2-Diols
Products
Time (h)
3
Yield (%)
90
Obs. Mp (ꢀC)
Lit. Mp (ꢀC)ref
238–240
239–24123
F
OH
N
F
OH
N
H
F
1j
4j
11
4
89
257–259
Br
Cl
Cl
OH
N
Cl
Br
Br
N
H
OH
4k
1k
12
13
2.5
4
95
88
255–257
263–265
256–25854
265–26759
OH
OH
N
OH
OH
N
H
HO
1l
4l
Cl
OH
Cl
N
Cl
N
OH Cl
H
Cl
1m
Cl
4m
14
15
2
4
96
89
219–221
263–265
218–22036
O
O
O
N
OH
O
N
H
OH
1n
O
4n
O
F
F
Cl
OH
N
N
OH Cl
H
F
Cl
1o
4o
and 13C NMR (100 MHz) spectra were recorded in
CDCl3 and DMSO-d6 with TMS as internal standard
using a Bruker spectrometer. Chemical shifts are
expressed in δ ppm. Elemental analyses were carried
out using an Elemental Vario Micro Cube Rapid Ana-
lyzer. Lead tetraacetate is a solid compound, and its
purity is ≥99.99%.
room temperature for 5 min. Then, benzil (0.42 g, 2 mmol)
and ammonium acetate (0.32 g, 4.2 mmol) were added to a
round-bottom flask fitted with a reflux condenser and a
guard tube. Then reaction mixture was heated at 70ꢀC in
an oil bath for 3 h. The reaction was allowed to cool to
room temperature, and 10 mL of water was added. The
resulting precipitate was collected by filtration and washed
with cold ethanol to afford the product. The crude product
was purified by recrystallization from ethanol.
Typical experimental procedure for the synthesis of
2,4,5-triphenyl-1H-imidazole (4a)
Lead tetraacetate (0.44 g, 1 mmol) was added to a
solution of 1,2-diphenylethane-1,2-diol (0.21 g, 1 mmol) in
dry ethanol (10 mL). The reaction mixture was stirred at
CONCLUSION
In conclusion, we have developed an efficient and
facile method for the synthesis of 2,4,5-triphenyl
4
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One-Pot Synthesis of Imidazoles
Step 1.
2-(4-Ethoxyphenyl)-4,5-diphenyl-1H-imidazole (4d).
O
H
A pale brown solid, 309 mg (91% yield). IR (ATR,
OH
Pb(OAc) 4
1
cm−1): 3330 (NH); mp 218–220ꢀC. H NMR (CDCl3,
2 AcOH
+
Pb(OAc)
2
+
2
OH
400 MHz): δ 10.03 (s, 1H, NH), 8.41–6.84 (m, 13H, Ar-
H), 3.98 (m, 2H, CH2), 1.39 (m, 3H, CH3) ppm. Anal.
Calcd for C23H20N2O: C, 81.15; H, 5.92; N, 8.23;
found: C, 81.12; H, 5.90; N, 8.21%.
Step 2.
HOAc
HOAc
OH
HN
H2
N
O
NH4OAc
+
NH3
H2
O
AcOH
2-(3-Bromo-4-methoxyphenyl)-4,5-diphenyl-1H-imi-
dazole (4e). A pale brown solid, 372 mg (92% yield). IR
(ATR, cm−1): 3320 (NH); mp 231–233ꢀC. 1H NMR
(DMSO-d6, 400 MHz): δ 12.59 (s, 1H, NH, D2O
exchangeable), 8.30–7.19 (m, 13H, Ar-H), 3.90 (s, 3H,
OCH3) ppm. 13C NMR (DMSO-d6, 100 MHz): δ
155.3, 144.0, 136.9, 135.0, 130.9, 129.4, 128.5, 128.2,
128.1, 128.0, 127.6, 127.0, 126.4, 125.8, 124.4, 112.8,
110.8, 56.3 ppm. Anal. Calcd for C22H17N2OBr: C,
65.20; H, 4.23; N, 6.91; found: C, 65.18; H,
4.20; N, 6.88%.
imine
O
O
O
NH2
OH
NH4OAc
NH
+
NH3
O
HOAc
H2
O
HOAc
intermediate
HOAc
NH
NH
N
N
N
HN
O
H
OH
HOAc
H2
O
HOAc
AcOH
H
N
2-(4-Nitrophenyl)-4,5-diphenyl-1H-imidazole (4f ).
A brown solid, 279 mg (82% yield). IR (ATR, cm−1):
3320 (NH); mp 240–242ꢀC. 1H NMR (CDCl3,
400 MHz): δ 10.02 (s, 1H, NH), 8.26–7.26 (m, 14H,
Ar-H) ppm. Anal. Calcd for C21H15N3O2: C, 73.89; H,
4.43; N, 12.31; found: C, 73.88; H, 4.41; N, 12.28%.
2-(3-Bromo-4-chlorophenyl)-4,5-diphenyl-1H-imida-
zole (4g). A white solid, 364 mg (89% yield). IR (ATR,
N
Fig. 2 Plausible mechanism for the formation of
imidazole derivatives.
imidazole derivatives via a one-pot, three-component
condensation reaction between 1,2-diols, benzil, and
ammonium acetate. The current strategy can be used to
decrease the number of steps in a multistep synthesis.
1
cm−1): 3335 (NH); mp 255–257ꢀC. H NMR (DMSO-
d6, 400 MHz): δ 12.77 (s, 1H, NH), 8.41–7.21 (m, 13H,
Ar-H) ppm. 13C NMR (DMSO-d6, 100 MHz): δ 159.2,
156.8, 143.1, 137.3, 134.8, 130.7, 129.7, 128.6, 128.4
(2C), 128.2, 128.1, 127.8, 127.0, 126.6, 126.4, 126.3,
117.2, 117.0, 108.5, 108.2 ppm. Anal. Calcd for
C21H14N2BrCl: C, 61.56; H, 3.44; N, 6.84; found: C,
61.54; H, 3.43; N, 6.82%.
4,5-Diphenyl-2-p-tolyl-1H-imidazole (4h). A white
solid, 285 mg (92% yield). IR (ATR, cm−1): 3312 (NH);
mp 233–235ꢀC. 1H NMR (DMSO-d6, 400 MHz): δ
12.56 (s, 1H, NH), 7.98–7.19 (m, 14H, Ar-H), 2.35 (s,
3H, CH3) ppm. Anal. Calcd for C22H18N2: C,
85.13; H, 5.85; N, 9.03; found: C, 85.11; H,
5.82; N, 9.02%.
2-(4-Bromophenyl)-4,5-diphenyl-1H-imidazole (4i).
A white solid, 341 mg (91% yield). IR (ATR, cm−1):
3320 (NH); mp 248–250ꢀC. 1H NMR (DMSO-d6,
400 MHz): δ 12.61 (s, 1H, NH), 7.79–7.22 (m, 14H,
Ar-H) ppm. Anal. Calcd for C21H15N2Br: C, 67.21; H,
4.03; N, 7.47; found: C, 67.18; H, 4.02; N, 7.45%.
Spectral data of imidazole compounds
2,4,5-Triphenyl-1H-imidazole (4a). A pale brown
solid, 284 mg (96% yield). IR (ATR, cm−1): 3325 (NH);
mp 275–277ꢀC. 1H NMR (DMSO-d6, 400 MHz): δ
9.22 (s, 1H, NH), 8.05–6.73 (m, 15H, Ar-H) ppm.
Anal. Calcd for C21H16N2: C, 85.11; H, 5.44; N, 9.45;
found: C, 85.09; H, 5.43; N, 9.42%.
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (4b).
A white solid, 293 mg (89% yield). IR (ATR, cm−1):
3328 (NH); mp 234–236ꢀC. 1H NMR (DMSO-d6,
400 MHz): δ 12.79 (s, 1H, NH), 8.15–7.21 (m, 14H,
Ar-H) ppm. Anal. Calcd for C21H15N2Cl: C, 76.24; H,
4.57; N, 8.47; found: C, 76.22; H, 4.56; N, 8.44%.
2-(3-Chlorophenyl)-4,5-diphenyl-1H-imidazole (4c).
A white solid, 297 mg (90% yield). IR (ATR, cm−1):
3315 (NH); mp 245–247ꢀC. 1H NMR (CDCl3,
400 MHz): δ 11.25 (s, 1H, NH), 8.40–7.24 (m, 14H,
Ar-H) ppm. Anal. Calcd for C21H15N2Cl: C, 76.24; H,
4.57; N, 8.47; found: C, 76.22; H, 4.56; N, 8.44%.
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Article
Jagadishbabu and Shivashankar
2-(4-Fluorophenyl)-4,5-diphenyl-1H-imidazole (4j).
ACKNOWLEDGMENT
A pale brown solid, 282 mg (90% yield). IR (ATR,
This work was financially supported by the
Council of Scientific and Industrial Research (CSIR),
New Delhi, India (www.csirhrdg.res.in; no. 02(0172)/
13/EMR-II dated: Oct. 21, 2013; May 29, 2014; and
Oct. 19, 2016).
1
cm−1): 3322 (NH); mp 239–241ꢀC. H NMR (DMSO-
d6, 400 MHz): δ 12.80 (s, 1H, NH), 7.60–7.23 (m, 12H,
Ar-H) ppm. Anal. Calcd for C21H15N2F: C, 80.24; H,
4.81; N, 8.91; found: C, 80.22; H, 4.78; N, 8.90%.
2-(4-Bromo-3-chlorophenyl)-4,5-diphenyl-1H-imida-
zole (4k). A white solid, 364 mg (89% yield). IR (ATR,
Supporting information
Additional supporting information is available in
the online version of this article.
1
cm−1): 3315 (NH); mp 257–259ꢀC. H NMR (DMSO-
d6, 400 MHz): δ 12.76 (s, 1H, NH), 8.27–7.22 (m, 13H,
Ar-H) ppm. 13C NMR (DMSO-d6, 100 MHz): δ 158.2,
155.7, 143.2, 137.3, 134.8, 130.7, 128.6, 128.2, 128.1
(2C), 127.8, 127.0, 126.8, 126.6, 125.7 (2C), 120.0, 119.8,
117.4, 117.2 ppm. Anal. Calcd for C21H14N2ClBr: C,
61.56; H, 3.44; N, 6.84; found: C, 61.53; H,
3.42; N, 6.83%.
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4-(4,5-Diphenyl-1H-imidazol-2-yl)phenol (4l).
A
white solid, 296 mg (95% yield). IR (ATR, cm−1): 3324
(NH); mp 256–258ꢀC. 1H NMR (DMSO-d6,
400 MHz): δ 12.58 (s, 1H, NH), 9.51 (s, 1H, OH),
7.54–6.76 (m, 14H, Ar-H) ppm. Anal. Calcd for
C21H16N2O: C, 80.75; H, 5.16; N, 8.97; found: C,
80.72; H, 5.14; N, 8.96%.
2-(2,6-Dichlorophenyl)-4,5-diphenyl-1H-imidazole
(4m). A white solid, 321 mg (88% yield). IR (ATR,
1
cm−1): 3310 (NH); mp 265–267ꢀC. H NMR (DMSO-
d6, 400 MHz): δ 12.72 (s, 1H, NH), 7.65–7.20 (m, 13H,
Ar-H) ppm. Anal. Calcd for C21H14N2Cl2: C, 69.05; H,
3.86; N, 7.67; found: C, 69.03; H, 3.83; N, 7.66%.
2-(3,4-Dimethoxyphenyl)-4,5-diphenyl-1H-imidazo-
le (4n). A white solid, 341 mg (96% yield). IR (ATR,
1
cm−1): 3332 (NH); mp 218–220ꢀC. H NMR (DMSO-
d6, 400 MHz): δ 12.01 (s, 1H, NH), 7.55–7.10 (m, 13H,
Ar-H), 3.87 (s, 3H, OCH3), 3.82 (s, 3H, OCH3) ppm.
Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N,
7.86; found: C, 77.50; H, 5.64; N, 7.83%.
2-(2-Chloro-6-fluorophenyl)-4,5-diphenyl-1H-imida-
zole (4o). A pale brown solid, 309 mg (89% yield). IR
(ATR, cm−1): 3325 (NH); mp 263–265ꢀC. 1H NMR
(DMSO-d6, 400 MHz): δ 12.81 (s, 1H, NH), 7.61–7.24
(m, 13H, Ar-H) ppm. 13C NMR (DMSO-d6,
100 MHz): δ 136.9, 134.9, 134.6, 134.5, 131.8, 131.7,
130.7, 129.7, 129.6, 129.2, 129.0, 128.7, 128.4, 128.1,
128.0, 127.8 (2C), 127.7, 127.1, 126.5, 125.7 ppm. ESI-
MS: [M + H] 349.3. Anal. Calcd for C21H14N2ClF: C,
72.31; H, 4.05; N, 8.03; found: C, 72.30; H,
4.03; N, 8.02%.
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