One-Pot Synthesis of Polysubstituted Imidazoles Based on Pd(OAc) 2 /Ce(SO 4) 2 /Bi(NO 3) 3 Trimetallic Cascade of Decarboxylation/Wacker-Type Oxidation/Debus-Radziszewski Reaction

Article abstract of DOI:10.1055/s-0037-1611835

A novel and highly efficient one-pot synthesis of polysubstituted imidazoles from α-hydroxyphenylacetic acids, diphenylacetylene, and amines has been achieved by Pd(OAc) ₂ /Ce(SO ₄) ₂ /Bi(NO ₃) ₃ trimetallic catalytic system. A series of control experiments showed that this overall reaction occurs through a one-pot cascade process combining the steps of decarboxylation of α-hydroxyphenylacetic acids, Wacker-type oxidation of diphenylacetylene, and Debus-Radziszewski annulation of aryl aldehydes and benzil generated in situ, as well as amines. This reaction represents a novel multicomponent reaction using α-hydroxyphenylacetic acids and diphenylacetylene as sources of aryl aldehydes and a β-diketone. This process exhibits a broad substrate scope and a good functional group tolerance to assemble the corresponding polysubstituted imidazoles in excellent yields (72-88percent) under mild conditions.

Full text of DOI:10.1055/s-0037-1611835

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
W. Sun et al.
Paper
Synthesis
One-Pot Synthesis of Polysubstituted Imidazoles Based on
Pd(OAc)2/Ce(SO4)2/Bi(NO3)3 Trimetallic Cascade of Decarboxyl-
ation/Wacker-Type Oxidation/Debus–Radziszewski Reaction
Wei Suna
Mingjuan Zhanga
Peilang Lia
Yiqun Li*a,b
Ph
Ph
OH
PdII/CeIV/BiIII
OH
R-NH2
+
NH4OAc
+
+
Ph
Ph
N
N
Ar
R
O
Ar
0
0
0
0-0
0
0
2-
3
3
0
3-1
7
3
0
25 examples
72–88% yield
a Department of Chemistry, Jinan University, Guangzhou
510632, P. R. of China
tlyq@jnu.edu.cn
b Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P. R. of China
Received: 13.03.2019
Cl
Accepted after revision: 25.04.2019
Published online: 27.05.2019
DOI: 10.1055/s-0037-1611835; Art ID: ss-2019-f0021-op
N
H
OH
O
O
N
N
n-Bu
HN
N
N
N
N
O
N
N
O
O
N
Abstract A novel and highly efficient one-pot synthesis of polysubsti-
tuted imidazoles from -hydroxyphenylacetic acids, diphenylacetylene,
and amines has been achieved by Pd(OAc)2/Ce(SO4)2/Bi(NO3)3 trimetal-
lic catalytic system. A series of control experiments showed that this
overall reaction occurs through a one-pot cascade process combining
the steps of decarboxylation of -hydroxyphenylacetic acids, Wacker-
type oxidation of diphenylacetylene, and Debus–Radziszewski annula-
tion of aryl aldehydes and benzil generated in situ, as well as amines.
This reaction represents a novel multicomponent reaction using -hy-
droxyphenylacetic acids and diphenylacetylene as sources of aryl alde-
hydes and a -diketone. This process exhibits a broad substrate scope
and a good functional group tolerance to assemble the corresponding
polysubstituted imidazoles in excellent yields (72–88%) under mild con-
ditions.
OH
N
Losartan
Olmesartan
O
OH
N
Ph
N
N
Cl
n-Bu
N
S
N
Ph
N
H
O
CO2H
NMe2
Trifenagrel
Eprosartan
Clotrimazole
Key words PdII/CeIV/BiIII trimetallic system, imidazole, decarboxyl-
ation, Wacker-type oxidation, Debus–Radziszewski reaction
Figure 1 Representative imidazole skeleton in some commercial phar-
maceuticals
Nitrogen-rich heterocycles bearing an imidazole struc-
tural scaffold are widely found in wide range of naturally
occurring compounds, pharmaceuticals, agrochemicals,
and essential intermediates.1 Many of imidazole derivatives
act as p38 MAP kinase inhibitors,2 B-Raf kinase inhibitors,3
glucagon receptor antagonists,4 anti-inflammatories,5 and
antitumor agents.6 Imidazole moiety also is an integral part
of many commercial drugs7 such as Losartan, Olmesartan,
Trifenagrel, Eprosartan, and Clotrimazole (Figure 1).
Due to their pharmacological and biological importance,
recently many efforts have been focused on the synthesis of
the privileged imidazole derivatives with diverse functional
groups. Typically, there are three main methods to con-
struct imidazole derivatives: (1) Debus–Radziszewski imid-
azole synthesis, that is, one-pot multicomponent reaction
(MCR) of 1,2-dicarbonyl compound/-hydroxyketone, alde-
hyde, primary amine and/or ammonia source (Scheme 1,
Path 1);7d,8 (2) transition-metal-catalyzed arylation of imid-
azoles/haloimidazoles (Scheme 1, Path 2);9 (3) MCRs of
amidine with aldehydes, ketones, nitroolefins, and alkynes,
respectively (Scheme 1, Path 3).10
These documented protocols have their own merits and
disadvantages, however, most employed substrates are con-
fined to 1,2-diketones, aldehydes, primary amines, ami-
dines, and nitroalkenes, thus leading to imidazoles with
poor functional group diversity.
Therefore, the development of a simple, effective, high-
yielding method to access this heterocyclic architecture
from readily available and easily extensible starting materi-
als is still of great demand. The commercially available -
hydroxyphenylacetic acids and alkynes can be viewed as
potential surrogates of aryl aldehydes and 1,2-dicarbonyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

B
W. Sun et al.
Paper
Synthesis
To explore the feasibility of our strategy, we began our
study by exerting -hydroxyphenylacetic acid, diphenyl-
acetylene, and ammonium acetate as a model reaction,
which was conducted in the presence of various catalytic
system. The results are summarized in Table 1. Initially,
when the common catalyst such as Pd(OAc)2,
Ce(SO4)2·4H2O, and Bi(NO3)3·5H2O were employed, no prod-
uct was observed (Table 1, entries 1–3). Then we combined
Pd(OAc)2 with Bi(NO3)3·5H2O, and Ce(SO4)2·4H2O with
Bi(NO3)3·5H2O, as well as Pd(OAc)2 with Ce(SO4)2·4H2O as a
binary catalyst; here also no product or trace amount of
product was detected (entries 4–7). To our delight, we
found that the desired product was obtained in 40% yield
when Bi(NO3)3·5H2O was added, suggesting that all three
Pd2+/Ce4+/Bi3+ metals are required (entry 8). These results
encouraged us to investigate the effect of Bi(NO3)3 on the
reaction in order to further increase the yield. Obvious im-
pact of molar ratio of Ce(SO4)2·4H2O and Bi(NO3)3·5H2O on
the reaction was observed on the model (entries 8–13). It
was found that the Ce/Bi molar ratio of 1/2 is the best (entry
10). In addition, PdCl2 is slightly inefficient in place of
Pd(OAc)2 (entry 11). It should be noted that pivalic acid
(PivOH) plays a pivotal role in this transformation, as
demonstrated by the fact that the yields decreased when
PivOH was absent (entry 14). Other additives such as acetic
acid (AcOH), trifluoroacetic acid (TFA), and BF3·OEt2, tetra-
butylammonium bromide (TBAB), and sodium dodecylben-
zene sulfonate (SDBS) are less efficient instead of PivOH in
this model (entries 15–19). Further screening of solvents
demonstrated that DMSO/H2O (4:1 v/v) was the most suit-
able solvent (entry 10) among neat DMSO, DMF, H2O, 1,4-
dioxane, toluene, and dichloromethane (entries 21–27).
Lower yield was obtained when the reaction was per-
formed in DMF under nitrogen atmosphere compared with
the reaction done in the air (entry 23). Moreover, the model
reaction run successfully in DMSO/H2O (4:1 v/v) under in-
ert atmosphere, which illustrated DMSO serves an oxidant
in this reaction (entry 20). For practical application, good
stability and reusability of the catalytic system are highly
preferable. Along this line we have investigated the recy-
clability of trimetallic catalysts for the model reaction. After
the post-treatment process of the reaction, the mixture was
extracted with ethyl acetate to leave the catalysts in the
bottom of Schlenk tube. Then they were reused directly for
the next run without any further treatment. The experi-
ment result showed that the reused co-catalysts lose their
catalytic performance and afford no desire products (entry
10).
(1) Debus–Radziszewski imidazole synthesis
Ph
Ph
O
O
R-NH2
Lewis acid
Ph
N
N
+
+
Ph
R
Ar
H
NH4OAc
O
Ar
(2) Arylation of imidazole
(a) N-arylation
N
N
Ar-X (X = I, Br)
or
+
N
H
N
[Cu]
Ar-B(OH)2
Ar
(b) C-arylation
N
N
[Pd]
Ar-Br
+
Ar
N
N
Me
Me
(c) Suzuki-type synthesis of imidazoles
N
N
[Pd]
+
Ar-B(OH)2
X
N
R
Ar
N
R
X = I, Br
(3) Synthesis of imidazole from amidine
R1
N
NH
[Fe]
R3
OHC R1
R2
+
+
R2
N
H
N
R3
R3
R4
NH
O
N
CBr4
R2
R4
R1
N
H
R3
R1
N
R2
Ar3
R
Ar1
Ar2
H
N
[In]
O2N
N
Ar
+
+
Ar2
N
Ar1
H
R
N
R3
N
NH
[Cu]
R2
R3
R1
H
R1
N
N
R2
H
(4) This work
Ph
Ph
Ph
OH
PdII/CeIV/BiIII
NH4OAc
N
N
OH
R-NH2
+
+
R
Ar
O
Ph
Ar
Scheme 1 Synthetic strategies for the construction of substituted im-
idazoles
compounds. We assume that it may be a new protocol for
the synthesis of polysubstituted imidazoles from -hy-
droxyphenylacetic acids with alkynes in the presence of a
suitable catalytic system. In light of this hypothesis, we
With the optimized conditions in hand, the scope and
generality of this reaction were explored. Various -hy-
droxyphenylacetic acids with electron-withdrawing and
electron-donating group on the phenyl ring were first ex-
amined and the results are shown in Scheme 2. It was found
that the electronic effect of the substrates has no apparent
impact on the product yields (products 5a–i). The substitu-
present here the first successful attempt on
a
Pd(OAc)2/Bi(NO3)3/Ce(SO4)2 trimetallic system catalyzed
MCRs of -hydroxyphenylacetic acids, diphenylacetylene,
primary amines and/or ammonium acetate for construction
of polysubstituted imidazoles under mild conditions.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

C
W. Sun et al.
Paper
Synthesis
Table 1 Optimization of Conditions for the Formation of 5aa
OH
OH
N
Ph
Ph
NH4OAc
+
+
O
N
H
1
2
4
5a
Entry
Catalyst (mol%)
Solvent (v/v)
Additive (equiv)
Yield (%)b
1
2
Pd(OAc)2 (5)
Ce(SO4)2 (10)
Bi(NO3)3 (10)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO
–
n.d.
n.d.
n.d.
n.d.
n.d.
trace
trace
40
–
3
–
4
Pd(OAc)2 (5)/Bi(NO3)3 (20)
Ce(SO4)2 (10)/Bi(NO3)3 (20)
Pd(OAc)2 (5)/Ce(SO4)2 (10)
Pd(OAc)2 (5)/Ce(SO4)2 (10)
–
5
–
6
–
7
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
–
8
Pd(OAc)2 (5)/Ce(SO4)2 (10)/Bi(NO3)3 (10)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (20)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
PdCl2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (10)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (30)/Bi(NO3)3 (20)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
9
58
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
84 (trace)c
80
72
36
70
AcOH (2)
TFA (2)
BF3·OEt2 (0.5)
TBAB (2)
SDBS (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
40
n.d.
n.d.
34
trace
86d
65
H2O
n.d.
15d (68)e
trace
trace
n.d.
n.d.
DMF
1,4-dioxane
EtOH
toluene
CH2Cl2
a All reactions were carried out with 1a (1.5 mmol), 2 (1.0 mmol), 4 (3.0 mmol), and a catalytic amount of the catalyst in solvent (2 mL) at 120 °C for 10 h.
b Isolated yields. n.d.: Not detected.
c The yield was based on the next run.
d Under N2 atmosphere.
e Prolonged to 48 h in the air.
ents (Cl, Br, NO2) on the substrate remain intact under the
present reaction conditions and afforded good product
yields.
Having successfully evidenced the domain of -hy-
droxyphenylacetic acids by this novel approach, we were
encouraged to conduct further exploration on the scope of
amines, and the results are shown in Scheme 3. As can be
seen from the results, the electronic effect of substituents
on the aromatic ring of anilines exerted no significant effect
on the reaction and produced the desired imidazoles in ex-
cellent yields (products 5j–q). These results indicated that
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

D
W. Sun et al.
Paper
Synthesis
OH
OH
OH
Ph
R2NH2
OH
+
N
O
N
Ph
Ph
NH4OAc
+
O
3
R1
Ph
N
H
+
1
2
R
N
NH4OAc
R
R2
R1
MeO
MeO
2
4
5
1
4
5
Ph
Ph
Ph
Ph
N
N
Ph
Ph
N
N
N
N
Ph
Ph
N
H
N
H
Ph
Ph
N
H
Ph
N
Ph
N
Ph
Ph
N
Br
Cl
Ph
Ph
Ph
Cl
5a, 84%
5d, 88%
5g, 84%
5b, 85%
5c, 83%
5j, 72%
5k, 74%
5l, 79%
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
O2N
Ph
N
H
Ph
Me
Ph
N
H
Ph
N
N
H
Ph
N
Ph
MeO
MeO
Me
5e, 86%
5f, 75%
Ph
Ph
Ph
Me
OMe
Cl
N
Cl
N
OMe
N
5m, 84%
5n, 88%
5o, 86%
MeO
HO
Ph
N
H
Ph
Ph
N
N
H
Ph
Ph
Ph
H
N
N
N
N
5h, 82%
5i, 85%
Ph
Ph
Ph
N
Ph
N
Scheme 2 Scope of -hydroxyphenylacetic acids for the synthesis of
polysubstituted imidazoles under optimal conditions. Isolated yield of
each product is shown.
OMe
Me
5p, 88%
5q, 86%
5r, 80%
the reaction may be extensible. Then we turned our atten-
tion toward benzylamines and found the benzylamines re-
acted well under the optimal condition to give the corre-
sponding imidazoles in excellent yields (products 5r–x)
(Scheme 3).
Ph
Ph
N
N
N
N
Ph
Ph
Br
Cl
To gain further insights into the reaction mechanism,
some control experiments were carried out (Table 2). First,
the decarboxylative reaction of -hydroxyphenylacetic ac-
ids was conducted in various of catalytic system to clarify
the role of catalyst. We found that the decarboxylation pro-
cedure still proceeded without the presence of Bi(NO3)3 (Ta-
ble 2, a). This result indicated that Pd(OAc)2 and Ce(SO4)2
play a crucial impact on the decarboxylation. Subsequently,
diphenylacetylene was employed under aforementioned
optimized conditions to afford the desired benzil via
Wacker-type oxidation11 in 97% yield (Table 2, b). Unlike the
decarboxylative procedure (Table 2, a), Pd(OAc)2, Ce(SO4)2,
and Bi(NO3)3 are all indispensable for the reaction; the de-
sired product could not be obtained in the absence of any
one of them. Meanwhile, in case the catalytic activity is not
high enough, pivalic acid is applied to enhance reactivity
(Table 2, b). The improvement of catalytic efficiency may be
attributed to the formation of highly electrophilic
Pd+(PivO)12 and to the formation of a Pd+(PivO)/Ce4+/Bi3+--
5s, 76%
5t, 78%
X ray of 5t
Ph
Ph
Ph
OMe
N
N
N
Ph
N
Ph
Ph
N
N
Me
MeO
5u, 84%
5v, 80%
5w, 80%
Ph
NO2
N
Ph
N
5x, 76%
Scheme 3 Scope of amines for the synthesis of polysubstituted imid-
azoles under optimal conditions. Isolated yield of each product is
shown.
complex intermediate through the coordination of the C≡C
bond with Pd+(PivO), Ce4+, and Bi3+ species.13b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

E
W. Sun et al.
Paper
Synthesis
Table 2 Control Experiments
termediates, the rates of substrate conversion and product
outcome were measured by GC/MS analysis (Figure 2). As
can be seen, imidazole yields increased rapidly with the
conversion of hydroxyphenylacetic acid and 1,2-dipheny-
lacetylene. These results suggest that aryl aldehyde and
benzil should be the true intermediates in this transforma-
tion. Finally, when benzaldehyde, benzil, and ammonium
acetate were subjected to standard conditions, the desired
product was successfully isolated in 88% yield (Table 2, c).
a) Decarboxylation of mandelic acid
OH
Catalyst
CO2H
CHO
OH
PivOH (2 equiv)
+
O
DMSO/H2O (1:4), 120 °C
6a
Catalyst (mol%)
Pd(OAc)2 (5)
Yield (%)a of 6a
n.d.
42
Ce(SO4)2 (20)
Bi(NO3)3 (40)
n.d.
95
Pd(OAc)2 (5)/Ce(SO4)2 (20)
b) Wacker-type oxidation
Catalyst
O
PivOH (2 equiv)
Ph
Ph
Ph
Ph
DMSO/H2O (1:4), 120 °C
O
7a
Catalyst (mol%)
Pd(OAc)2 (5)
Ce(SO4)2 (20)
Bi(NO3)3 (40)
Yield (%)a of 7a
n.d.
n.d.
n.d.
12
Pd(OAc)2 (5)/Ce(SO4)2 (20)
Figure 2 (a) -Hydroxyphenylacetic acid, (b) diphenylacetylene, (c)
2,4,5-triphenyl-1H-imidazole, (d) 2,4,5-triphenyloxazole.
Pd(OAc)2 (5)/Bi(NO3)3 (40)
n.d.
n.d.
97
Ce(SO4)2 (20)/Bi(NO3)3 (40)
On the basis of above experimental results and previous
reports,13 a plausible mechanism for the formation of sub-
stituted imidazole from hydroxyphenylacetic acids, diphe-
nylacetylene, and amines described herein is proposed in
Scheme 4. In cycle I, the first process involves an anion ex-
change of pivalate with Pd(OAc)2 to generate Pd(OPiv)2. Fur-
ther anion exchange of Pd(OPiv)2 with hydroxyphenylacetic
acid affords the palladium carboxylate intermediate, which
undergoes a direct oxidative decarboxylation to the corre-
sponding aryl aldehydes. In cycle II, the highly electrophilic
cationic species Pd+(OPiv) is generated in situ through
bonding pivalate by using PivOH as an additive.12 The cat-
ionic Pd+(OPiv) species combines with Ce4+ and Bi3+ to form
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
c) Debus–Radziszewski imidazole synthesis
O
Ph
Ph
CHO
Ph
Catalyst
N
O
PivOH (2 equiv)
+
Ph
N
H
DMSO/H2O (1:4), 120 °C
NH4OAc
5a
Catalyst (mol%)
Yield (%) of 5a
Pd(OAc)2 (5)/Ce(SO4)2 (20)/Bi(NO3)3 (40)
a n.d. = not detected.
84
a
Pd(OPiv)2/Ce4+/Bi3+--complex intermediate,13b which
should greatly activate the C≡C bond of the alkyne through
the coordination to generate the acceptors of DMSO. The
nucleophilic addition of DMSO to the thus generated -
complex intermediate followed by the release of Me2S and
the addition of another DMSO produces a keto alcohol-like
intermediate, which proceeds to afford the corresponding
Remarkably, the recent reports for conversion of 1,2-di-
phenylacetylene into benzil were performed in the pres-
ence of an abnormal NHC-RuII complex catalyst, [bis(trifluo-
roacetoxy)iodo]benzene (PIFA), or need a long-term process
(over 24 h) under hash condition.14 These results showed
that our Pd(OAc)2/Ce(SO4)2/Bi(NO3)3 trimetallic system ex-
hibited much more catalytic activity than the documented
protocols. These control experiments of decarboxylation
and Wacker-type oxidation suggest that aryl aldehyde and
benzil should be the true intermediates. To confirm that the
process commences with the formation of these two key in-
diphenyl
diketone
derivatives
along
with
the
Pd+(OPiv)/Ce4+/Bi3+ trimetallic species and Me2S. Noticeably,
the -complex leads to a more efficient nucleophilic attack
of DMSO onto the activated C≡C bond of the alkyne than
Pd(OAc)2 alone, thus affording more efficient alkyne oxida-
tion. In cycle III, the reaction starts with formation of benz-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

F
W. Sun et al.
Paper
Synthesis
aldehyde and benzil from hydroxyphenylacetic acids (cycle
I) and diphenylacetylene (cycle II), respectively. Then, the
condensation of the benzaldehyde with primary amine
and/or ammonia generates the diamine intermediate. Final-
ly, the condensation of diamine intermediate with benzil
generated in situ leads to cyclization, dehydration, and [1,5]
hydrogen shift and eventually to the formation of substitut-
ed imidazoles.
In summary, a novel and facile Pd(OAc)2/Ce(SO4)2/Bi(NO3)3
trimetallic catalytic system has been developed and applied
to the construction of a diverse range of multisubstituted
imidazoles starting from readily available -hydroxyphenyl-
Pd(OAc)2
directing group
OH
PivOH
leaving group
OH
Ph
Ce3+
O
Pd(OPiv)2
PivOH
Pd OPiv
PivOH
Ce4+
HO
cycle I
Pd(0)
O
+
PivOH
Ph
O
CO2
O
RNH2
Ph
Ph
– H2O
Ph
Ph
H
N
N
N
H
NHR
H
Ph
Ph
N
R
Ph
O
Ph
Ph
R
H
NH4OAc
NH3
cycle III
Ph
H
N
OH
Ph
NH2
RHN
O
NHR
Ph
O
Ph
+
Me2S
Ph
O
Pd(OAc)2
PivOH
Pd+(OPiv)
S
PivOH
cycle II
Ph
O
Pd(OPiv)
O
Ph
Me2S
Ph
Ph
O
S
Ph
O
Pd(OPiv)
Ph
Pd+(OPiv)
Ph
Ph
S
Ce4+/Bi3+
Ce4+/Bi3+
O
S
Scheme 4 Plausible mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

G
W. Sun et al.
Paper
Synthesis
acetic acids, diphenylacetylene, primary amine, and ammo-
nium acetate. Various substituents in -hydroxyphenyl-
acetic acids, anilines, and benzylamines are tolerated well
in this approach. This operationally practical protocol
might be a useful and widely applicable pathway to con-
struct valuable scaffolds of complex molecules in medicinal,
organic, and material chemistry.
1H NMR (300 MHz, DMSO-d6):  = 12.98 (s, 1 H), 8.17 (d, J = 8.6 Hz, 2
H), 7.55 (d, J = 8.5 Hz, 6 H), 7.35 (dt, J = 14.5, 6.7 Hz, 6 H).
13C NMR (100 MHz, DMSO-d6):  = 144.91, 136.03, 133.18, 132.66,
130.06, 129.98, 129.63, 129.19, 128.87, 128.23, 127.69, 127.42.
MS (ESI): m/z (%) = 331.1 [M + H]+.
2-(4-Bromophenyl)-4,5-diphenyl-1H-imidazole (5c)
Off-white solid; yield: 310.5 mg (83%); mp 261–262 °C (Lit.16 mp
260–262 °C).
IR (KBr): 3025, 2837, 1604, 1485, 1448, 1088 cm–1
1H NMR (300 MHz, DMSO-d6):  = 12.81 (s, 1 H), 8.05 (d, J = 8.6 Hz, 2
H), 7.69 (d, J = 8.6 Hz, 2 H), 7.59–7.20 (m, 10 H).
13C NMR (100 MHz, DMSO-d6):  = 144.93, 137.79, 135.44, 132.14,
131.37, 129.99, 129.14, 129.07, 128.89, 128.67, 128.34, 127.57,
127.54, 127.08, 121.86.
.
All chemicals were purchased from Aladdin, Alfa Aesar, Inochem, and
Acros and used without further purification. Reactions were carried
out in a Schlenk tube equipped with a stirring bar. The reaction tem-
peratures were maintained by thermostat-controlled oil baths. Reac-
tion procedures were monitored by TLC and Shimadzu QP2010 plus
gas chromatography–mass chromatography (GC-MS). Melting point-
ing was measured by an Electrothermal X6 microscopic digital melt-
ing pointing apparatus. 1H NMR spectra were recorded on a Bruker
300 Advance spectrometer (300 MHz) at 25 °C with CDCl3 or DMSO-
d6 as solvent and TMS as internal standard; their residual protons
were designated to 7.26 and 2.52 ppm, respectively. 13C NMR spectra
were recorded on a Bruker 300 Advance spectrometer (100 MHz) at
25 °C with CDCl3 or DMSO-d6 as solvent; the chemical shifts were at-
tributed to 77.16 ppm (CDCl3) and 39.5 ppm (DMSO-d6). Fourier
transform infrared (FT-IR) spectra were recorded from KBr pellets on
a Bruker Equinox-55 spectrophotometer.
MS (ESI): m/z (%) = 375.1 [M + H]+.
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (5d)
Off-white solid; yield: 287.0 mg (88%); mp 232–234 °C (Lit.15 mp
231–233 °C).
IR (KBr): 3025, 2961, 1612, 1496, 1449, 1255 cm–1
1H NMR (300 MHz, DMSO-d6):  = 12.54 (s, 1 H), 8.05 (d, J = 8.8 Hz, 2
H), 7.59–7.21 (m, 10 H), 7.06 (d, J = 8.8 Hz, 2 H), 3.82 (s, 3 H).
.
13C NMR (100 MHz, DMSO-d6):  = 159.87, 146.10, 137.23, 135.79,
131.71, 130.08, 129.98, 129.09, 128.82, 128.62, 128.12, 128.07,
127.52, 127.17, 126.87, 123.60, 114.55, 55.66.
2,4,5-Trisubstituted 1H-Imidazoles; General Procedure
1,2-Diphenlyacetylene (1.0 mmol), the respective -hydroxyphenyl-
acetic acid (1.5 mmol), pivalic acid (2.0 mmol), Pd(OAc)2 (5 mol%),
Ce(SO4)2·4H2O (20 mol%), and Bi(NO3)3 (40 mol%) were dissolved in
the reaction solvent [DMSO/H2O (4:1 v/v), 2 mL] in a 25 mL Schlenk
tube and the contents were stirred at 120 °C for 2 h. After that
NH4OAc (3.0 mmol), and for the preparation of 1-substituted product,
the respective primary amine (1.0 mmol) were added and further
stirred at 120 °C for 10 h. The process was tracked by TLC or GC-MS.
Upon completion of the reaction, the mixture was cooled to r.t. and
extracted with CH2Cl2. The combined organic phases were successive-
ly washed by brine and H2O, and dried (Na2SO4). The solvent was re-
moved on a rotary evaporator and the crude product was purified by
PTLC or column chromatography using EtOAc/n-hexane (1:6, v/v) to
afforded the desire pure product.
MS (ESI): m/z (%) = 327.1 [M + H]+.
4,5-Diphenyl-2-(p-tolyl)-1H-imidazole (5e)
Off-white solid; yield: 266.8 mg (86%); mp 227–229 °C (Lit.15 mp
228–230 °C).
IR (KBr): 3035, 2857, 1602, 1500, 1487, 1449 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 12.62 (s, 1 H), 7.99 (d, J = 8.2 Hz, 2
H), 7.61–7.46 (m, 4 H), 7.47–7.20 (m, 8 H), 2.35 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 146.14, 138.13, 137.39, 135.72,
131.62, 129.71, 129.10, 128.87, 128.63, 128.40, 128.16, 127.53,
126.92, 125.63, 21.37.
MS (ESI): m/z (%) = 311.2 [M + H]+.
2,4,5-Triphenyl-1H-imidazole (5a)
White solid; yield: 248.8 mg (84%); mp 270–272 °C (Lit.15 mp 270–
273 °C).
IR (KBr): 3036, 2850, 1600, 1488, 1460 cm–1
1H NMR (300 MHz, DMSO-d6):  = 12.71 (s, 1 H), 8.10 (d, J = 8.0 Hz, 2
2-(3-Nitrophenyl)-4,5-diphenyl-1H-imidazole (5f)
Orange solid; yield: 255.8 mg (75%); mp 312–314 °C (Lit.16 mp 311–
313 °C).
.
IR (KBr): 3441, 3055, 1599, 1485, 1448, 1365 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 13.11 (s, 1 H), 8.96 (s, 1 H), 8.52 (d,
J = 7.9 Hz, 1 H), 8.22 (d, J = 8.3 Hz, 1 H), 7.79 (t, J = 8.0 Hz, 1 H), 7.60–
7.24 (m, 10 H).
13C NMR (100 MHz, DMSO-d6):  = 148.80, 143.37, 136.00, 131.61,
130.85, 130.05, 129.95, 129.67, 129.16, 128.87, 128.72, 128.51,
127.59, 127.25.
H), 7.60–7.26 (m, 13 H).
13C NMR (100 MHz, DMSO-d6):  = 145.94, 137.54, 135.62, 131.53,
130.79, 129.14, 128.92, 128.71, 128.66, 128.24, 127.52, 126.97,
125.63.
MS (ESI): m/z (%) = 297.2 [M + H]+.
MS (ESI): m/z (%) = 342.1 [M + H]+.
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (5b)
Off-white solid; yield: 280.5 mg (85%); mp 264–265 °C (Lit.15 mp
260–262 °C).
2-(3-Methoxy-4-hydroxyphenyl)-4,5-diphenyl-1H-imidazole (5g)
White solid; yield: 287.4 mg (84%); mp 250–252 °C (Lit.16 mp 254–
256 °C).
IR (KBr): 3025, 2837, 1600, 1487, 1449, 1085 cm–1
.
IR (KBr): 3511, 3030, 2965, 1605, 1495, 1228 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

H
W. Sun et al.
Paper
Synthesis
1H NMR (300 MHz, DMSO-d6):  = 12.49 (s, 1 H), 7.68 (d, J = 2.0 Hz, 1
H), 7.62–7.50 (m, 5 H), 7.34 (t, J = 12.8 Hz, 5 H), 6.90 (d, J = 8.2 Hz, 1
H), 3.87 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 148.15, 147.56, 146.58, 128.85,
122.38, 118.85, 116.09, 109.80, 56.13.
2-(4-Methoxyphenyl)-1,4,5-triphenyl-1H-imidazole (5l)
White solid; yield: 307.7 mg (79%); mp 182–184 °C (Lit.18 mp 183–
185 °C).
IR (KBr): 3030, 1604, 1530, 1493, 1350 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.59 (d, J = 6.8 Hz, 2 H), 7.35 (d, J = 8.8
Hz, 2 H), 7.29–7.00 (m, 14 H), 6.76 (d, J = 8.8 Hz, 2 H), 3.76 (s, 3 H).
MS (ESI): m/z (%) = 343.1 [M + H]+.
13C NMR (100 MHz, CDCl3):  = 159.61, 146.90, 137.97, 137.21,
134.46, 131.14, 130.73, 130.48, 130.35, 129.08, 128.49, 128.33,
128.20, 128.16, 127.90, 127.44, 126.57, 123.04, 113.56, 55.23.
2-(2-Chlorophenyl)-4,5-diphenyl-1H-imidazole (5h)
Pale yellow solid; yield: 271.3 mg (82%); mp 189–191 °C (Lit.15 mp
190–192 °C).
MS (ESI): m/z (%) = 403.2 [M + H]+.
IR (KBr): 3025, 2837, 1597, 1482, 1445, 1082 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.41 (dd, J = 7.9, 1.7 Hz, 1 H), 8.01–7.94
(m, 2 H), 7.68–7.61 (m, 1 H), 7.50 (t, J = 7.8 Hz, 2 H), 7.46–7.36 (m, 1
H), 7.38–7.32 (m, 5 H), 7.31–7.26 (m, 2 H).
2-(4-Methoxyphenyl)-4,5-diphenyl-1-(p-tolyl)-1H-imidazole (5m)
Pale white solid; yield: 349.6 mg (84%); mp 180–182 °C (Lit.19 mp
176–178 °C).
13C NMR (100 MHz, CDCl3):  = 143.20, 134.94, 132.97, 130.90,
130.47, 129.93, 129.69, 129.63, 129.05, 128.69, 127.81, 127.60,
127.50.
IR (KBr): 3028, 1604, 1550, 1483, 1340 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.63–7.53 (m, 2 H), 7.36 (d, J = 8.9 Hz, 2
H), 7.21 (pd, J = 7.7, 7.0, 3.4 Hz, 6 H), 7.15–7.07 (m, 2 H), 7.03 (d, J = 8.1
Hz, 2 H), 6.90 (d, J = 8.2 Hz, 2 H), 6.76 (d, J = 8.9 Hz, 2 H), 3.76 (s, 3 H),
2.30 (s, 3 H).
MS (ESI): m/z (%) = 331.1 [M + H]+.
2-(2-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (5i)
White solid; yield: 277.2 mg (85%); mp 200–201 °C (Lit.15 mp 200–
202 °C).
13C NMR (100 MHz, CDCl3):  = 159.53, 146.93, 138.08, 137.88,
134.56, 131.15, 130.84, 130.54, 130.32, 129.70, 128.43, 128.30,
128.16, 128.13, 127.82, 127.42, 126.49, 123.19, 113.53, 55.22, 21.21.
IR (KBr): 3008, 2951, 1600, 1486, 1459, 1205 cm–1
.
MS (ESI): m/z (%) = 417.2 [M + H]+.
1H NMR (300 MHz, CDCl3):  = 8.49 (dd, J = 7.8, 1.8 Hz, 1 H), 7.58 (s, 4
H), 7.41–7.22 (m, 8 H), 7.11 (td, J = 7.5, 1.0 Hz, 1 H), 7.02–6.99 (m, 1
H), 4.01 (s, 3 H).
1-(4-Methoxyphenyl)-4,5-diphenyl-2-(p-tolyl)-1H-imidazole (5n)
White solid; yield: 366.3 mg (88%); mp 170–172 °C (Lit.20 mp 176–
177 °C).
13C NMR (100 MHz, CDCl3):  = 155.72, 144.05, 129.56, 128.65,
IR (KBr): 3030, 1604, 1547, 1473, 1342 cm–1
.
128.61, 127.81, 127.25, 126.82, 121.68, 118.11, 111.20, 55.91.
MS (ESI): m/z (%) = 327.1 [M + H]+.
1H NMR (300 MHz, CDCl3):  = 7.59 (dd, J = 8.2, 1.4 Hz, 2 H), 7.38–7.01
(m, 12 H), 7.01–6.90 (m, 2 H), 6.81–6.69 (m, 2 H), 3.76 (s, 3 H), 2.30 (s,
3 H).
1,2,4,5-Tetraphenyl-1H-imidazole (5j)
Pale white solid; yield: 268.0 mg (72%); mp 216–217 °C (Lit.17 mp
211–216 °C).
13C NMR (100 MHz, CDCl3):  = 159.04, 147.18, 138.07, 137.93,
134.56, 131.15, 130.88, 130.82, 129.98, 129.46, 128.84, 128.79,
128.33, 128.13, 127.83, 127.73, 127.40, 126.50, 114.17, 55.37, 21.31.
IR (KBr): 3055, 1600, 1500, 1350 cm–1
.
MS (ESI): m/z (%) = 417.2 [M + H]+.
1H NMR (300 MHz, CDCl3):  = 7.65–7.54 (m, 2 H), 7.46–7.40 (m, 2 H),
7.28–7.17 (m, 12 H), 7.12 (dd, J = 7.5, 2.2 Hz, 2 H), 7.03 (dd, J = 7.6, 2.1
Hz, 2 H).
1-(4-Chlorophenyl)-2-(4-methoxyphenyl)-4,5-diphenyl-1H-imid-
azole (5o)
13C NMR (100 MHz, CDCl3):  = 146.93, 138.25, 137.09, 134.40,
131.14, 130.87, 130.63, 130.48, 129.09, 128.99, 128.45, 128.37,
128.30, 128.28, 128.19, 128.13, 127.99, 127.44, 126.65.
Yellow solid; yield: 375.0 mg (86%); mp 175–177 °C (Lit.21 mp 176–
177 °C).
IR (KBr): 3060, 2950, 1479, 1458, 1072 cm–1
.
MS (ESI): m/z (%) = 373.2 [M + H]+.
1H NMR (300 MHz, CDCl3):  = 7.57 (dd, J = 8.2, 1.4 Hz, 2 H), 7.44–7.33
(m, 2 H), 7.30–7.17 (m, 8 H), 7.17–7.07 (m, 2 H), 7.01–6.89 (m, 2 H),
6.83–6.71 (m, 2 H), 3.77 (s, 3 H).
2-(4-Chlorophenyl)-1,4,5-triphenyl-1H-imidazole (5k)
Yellow solid; yield: 301.1 mg (74%); mp 160–162 °C (Lit.17 mp 160–
13C NMR (100 MHz, CDCl3):  = 159.26, 149.97, 145.86, 138.22,
134.25, 131.37, 131.10, 130.50, 130.06, 129.57, 129.37, 129.04,
128.40, 128.38, 128.20, 128.03, 127.35, 126.69, 114.36, 55.40.
165 °C).
IR (KBr): 3058, 3030, 2940, 1605, 1477, 1350, 1088 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.58 (d, J = 7.9 Hz, 2 H), 7.35 (d, J = 8.6
Hz, 2 H), 7.30–7.17 (m, 11 H), 7.11 (dd, J = 7.6, 2.1 Hz, 2 H), 7.03 (dd,
J = 7.7, 2.0 Hz, 2 H).
MS (ESI): m/z (%) = 437.1 [M + H]+.
1-(4-Methoxyphenyl)-2,4,5-triphenyl-1H-imidazole (5p)
Yellow solid; yield: 353.9 mg (88%); mp 175–176 °C (Lit.21 mp 175–
177 °C).
13C NMR (100 MHz, CDCl3):  = 145.76, 138.42, 136.87, 134.36,
134.20, 131.17, 131.09, 130.39, 130.12, 129.27, 128.94, 128.53,
128.40, 128.37, 128.23, 128.11, 127.39, 126.77.
IR (KBr): 3030, 1600, 1525, 1495, 1348 cm–1
.
MS (ESI): m/z (%) = 407.9 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

I
W. Sun et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3):  = 7.59 (d, J = 7.7 Hz, 2 H), 7.45 (dd, J = 6.7,
3.0 Hz, 2 H), 7.32–7.08 (m, 6 H), 6.95 (d, J = 8.4 Hz, 2 H), 6.75 (d, J = 8.4
Hz, 2 H), 3.76 (s, 3 H).
1-Benzyl-2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole (5u)
White solid; yield: 349.4 mg (84%); mp 158–160 °C (Lit.16 mp 159–
161 °C).
13C NMR (100 MHz, CDCl3):  = 159.10, 147.05, 138.09, 134.49,
131.15, 131.09, 130.74, 130.58, 129.85, 129.43, 128.93, 128.36,
128.20, 128.16, 128.12, 127.91, 127.41, 126.57, 114.21, 55.38.
IR (KBr): 3026, 1605, 1531, 1493, 1350 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.62–7.51 (m, 4 H), 7.34–7.27 (m, 3 H),
7.23–7.12 (m, 8 H), 6.93–6.86 (m, 2 H), 6.85–6.75 (m, 2 H), 5.06 (s, 2
H), 3.78 (s, 3 H).
MS (ESI): m/z (%) = 403.2 [M + H]+.
13C NMR (100 MHz, CDCl3):  = 160.12, 148.04, 137.84, 137.69,
134.57, 131.14, 131.09, 130.45, 129.80, 128.80, 128.62, 128.59,
128.10, 127.35, 126.82, 126.33, 126.01, 123.38, 114.04, 55.34, 48.24.
2,4,5-Triphenyl-1-(p-tolyl)-1H-imidazole (5q)
Light yellow solid; yield: 316.7 mg (86%); mp 177–179 °C (Lit.15 mp
176–177 °C).
IR (KBr): 3038, 2850, 1599, 1498, 1485, 1448 cm–1
MS (ESI): m/z (%) = 417.2 [M + H]+.
.
1H NMR (300 MHz, CDCl3):  = 7.59 (d, J = 7.7 Hz, 2 H), 7.44 (dd, J = 6.9,
2.9 Hz, 2 H), 7.28–7.10 (m, 11 H), 7.03 (d, J = 8.0 Hz, 2 H), 6.91 (d, J =
8.2 Hz, 2 H), 2.30 (s, 3 H).
1-Benzyl-4,5-diphenyl-2-(p-tolyl)-1H-imidazole (5v)
Brown solid; yield: 349.4 mg (80%); mp 162–165 °C (Lit.16 mp 165–
168 °C).
13C NMR (100 MHz, CDCl3):  = 146.96, 138.18, 138.14, 134.46,
134.44, 131.15, 130.94, 130.73, 130.57, 129.71, 128.97, 128.34,
128.23, 128.16, 128.12, 128.09, 127.92, 127.44, 126.59, 21.21.
IR (KBr): 3026, 2925, 1598, 1482, 1330 cm–1
1H NMR (300 MHz, CDCl3):  = 7.62–7.49 (m, 4 H), 7.35–7.08 (m, 13
.
H), 6.84–6.75 (m, 2 H), 5.09 (s, 2 H), 2.36 (s, 3 H).
MS (ESI): m/z (%) = 387.2 [M + H]+.
13C NMR (100 MHz, CDCl3):  = 149.98, 148.21, 138.86, 137.92,
137.66, 134.51, 131.09, 129.90, 129.30, 128.96, 128.78, 128.57,
128.08, 127.99, 127.32, 126.81, 126.33, 126.01, 48.28, 21.39.
1-Benzyl-2,4,5-triphenyl-1H-imidazole (5r)
Yellow solid; yield: 309.0 mg (80%); mp 166–167 °C (Lit.16 mp 161–
163 °C).
MS (ESI): m/z (%) = 401.2 [M + H]+.
IR (KBr): 3057, 1601, 1497, 1500, 1350 cm–1
.
1-Benzyl-2-(2-methoxyphenyl)-4,5-diphenyl-1H-imidazole (5w)
Yellow solid; yield: 330.0 mg (80%); mp 176–178 °C (Lit.22 mp 175–
178 °C).
1H NMR (300 MHz, CDCl3):  = 7.63 (dd, J = 6.7, 3.0 Hz, 2 H), 7.56 (d, J =
7.1 Hz, 2 H), 7.42–7.27 (m, 5 H), 7.25–7.05 (m, 9 H), 6.82–6.71 (m, 2
H), 5.08 (s, 2 H).
13C NMR (100 MHz, CDCl3):  = 148.10, 138.09, 137.57, 134.49,
131.10, 131.05, 130.96, 130.09, 129.10, 128.94, 128.83, 128.66,
128.63, 128.61, 128.12, 127.38, 126.82, 126.40, 126.04, 48.31.
IR (KBr): 3028, 1600, 1534, 1490, 1352 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.57 (d, J = 5.0 Hz, 3 H), 7.48 (d, J = 5.1
Hz, 1 H), 7.28–7.01 (m, 11 H), 6.98 (t, J = 5.0 Hz, 1 H), 6.92 (d, J = 5.7
Hz, 1 H), 6.67–6.62 (m, 2 H), 4.92 (s, 2 H), 3.76 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 157.47, 145.61, 137.81, 137.39,
134.67, 132.83, 131.41, 131.15, 130.94, 129.07, 128.75, 128.60,
128.44, 128.12, 127.99, 127.04, 126.76, 126.62, 126.14, 120.97,
110.94, 55.51, 48.24.
MS (ESI): m/z (%) = 387.2 [M + H]+.
1-Benzyl-2-(4-chlorophenyl)-4,5-diphenyl-1H-imidazole (5s)
White solid; yield: 319.2 mg (76%); mp 164–165 °C (Lit.16 mp 160–
162 °C).
MS (ESI): m/z (%) = 417.2 [M + H]+.
IR (KBr): 3060, 3029, 2939, 1600, 1477, 1356, 1087 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.57 (dd, J = 7.8, 4.4 Hz, 4 H), 7.33 (t, J =
1-Benzyl-2-(2-nitrophenyl)-4,5-diphenyl-1H-imidazole (5x)
Brown solid; yield: 327.7 mg (76%); mp 150–153 °C (Lit.23 mp 152–
8.0 Hz, 5 H), 7.25–7.08 (m, 8 H), 6.85–6.75 (m, 2 H), 5.07 (s, 2 H).
13C NMR (100 MHz, CDCl3):  = 146.86, 138.29, 137.34, 135.01,
134.29, 131.04, 130.78, 130.47, 130.27, 129.40, 128.91, 128.87,
128.81, 128.75, 128.18, 127.55, 126.82, 126.55, 125.89, 48.32.
155 °C).
IR (KBr): 3025 1608, 1530, 1490, 1353 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.12–8.06 (m, 1 H), 7.57–7.48 (m, 3 H),
7.45–7.30 (m, 6 H), 7.22–7.07 (m, 5 H), 6.72 (dd, J = 7.5, 2.0 Hz, 2 H),
4.87 (s, 2 H).
MS (ESI): m/z (%) = 421.1 [M + H]+.
1-Benzyl-2-(4-bromophenyl)-4,5-diphenyl-1H-imidazole (5t)
Light yellow solid; yield: 362.0 mg (78%); mp 170–172 °C (Lit.16 mp
171–174 °C).
13C NMR (100 MHz, CDCl3):  = 148.98, 143.07, 138.09, 136.62,
134.17, 133.28, 133.08, 131.16, 130.66, 130.42, 130.13, 129.00,
128.87, 128.45, 128.12, 127.55, 126.71, 126.55, 126.49, 124.72, 48.36.
IR (KBr): 3059, 3029, 2940, 1598, 1476, 1356, 1069 cm–1
.
MS (ESI): m/z (%) = 432.2 [M + H]+.
1H NMR (300 MHz, CDCl3):  = 7.52 (d, J = 13.1 Hz, 6 H), 7.35–7.11 (m,
11 H), 6.79 (d, J = 6.5 Hz, 2 H), 5.07 (s, 2 H).
Funding Information
13C NMR (100 MHz, CDCl3):  = 146.88, 138.36, 137.33, 134.31,
131.82, 131.04, 130.77, 130.52, 130.50, 129.86, 128.91, 128.82,
128.76, 128.70, 128.18, 127.56, 126.82, 126.56, 125.87, 123.29, 48.32.
We are grateful to the National Natural Science Foundation of China
(No. 21372099) for financial support.
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
3
7
2
0
9
9)
MS (ESI): m/z (%) = 465.1 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

J
W. Sun et al.
Paper
Synthesis
Supporting Information
2006, 1379. (d) Joo, J. M.; Touré, B. B.; Sames, D. J. Org. Chem.
2010, 75, 4911. (e) Lessi, M.; Panzetta, G.; Marianetti, G.;
Bellina, F. Synthesis 2017, 49, 4676. (f) Recnik, L.-M.; Hameid, M.
A. E.; Haider, M.; Schnürch, M.; Mihovilovic, M. D. Synthesis
2013, 45, 1387.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611835.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
(10) (a) Liu, X.; Wang, D.; Chen, Y.; Tang, D.; Chen, B. Adv. Synth.
Catal. 2013, 355, 2798. (b) Zhang, X.; Wu, P.; Fu, Y.; Zhang, F.;
Chen, B. Tetrahedron Lett. 2017, 58, 870. (c) Mitra, S.; Bagdi, A.
K.; Majee, A.; Hajra, A. Tetrahedron Lett. 2013, 54, 4982. (d) Li, J.;
Neuville, L. Org. Lett. 2013, 15, 1752.
(11) (a) Ren, W.; Xia, Y.; Ji, S.-J.; Zhang, Y.; Wan, X.; Zhao, J. Org. Lett.
2009, 11, 1841. (b) Yuan, L.-Z.; Hamze, A.; Alami, M.; Provot, O.
Synthesis 2017, 49, 504.
References
(1) (a) Roué, M.; Domart-Coulon, I.; Ereskovsky, A.; Djediat, C.;
Perez, T.; Bourguet-Kondracki, M.-L. J. Nat. Prod. 2010, 73, 1277.
(b) Morinaka, B. I.; Pawlik, J. R.; Molinski, T. F.; Amaranzoles, B.-
F. J. Org. Chem. 2010, 75, 2453. (c) Tsukamoto, S.; Kawabata, T.;
Kato, H.; Ohta, T.; Rotinsulu, H.; Mangindaan, R. E. P.; van Soest,
R. W. M.; Ukai, K.; Kobayashi, H.; Namikoshi, M. J. Nat. Prod.
2007, 70, 1658. (d) Maier, U. H.; Gundlach, H.; Zenk, M. H. Phy-
tochem. 1998, 49, 1791.
(12) (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y.
Science 2000, 287, 1992. (b) Thikekar, T. U.; Sun, C.-M. Adv.
Synth. Catal. 2017, 359, 3388.
(2) Sisko, J. J. Org. Chem. 1998, 63, 4529.
(13) (a) Favier, I.; Dunãch, E. Tetrahedron 2003, 59, 1823. (b) Xue, J.-
W.; Zeng, M.; Hou, X.; Chen, Z.; Yin, G. Asian J. Org. Chem. 2018,
7, 212. (c) Mori, S.; Takubo, M.; Yanase, T.; Maegawa, T.;
Monguchi, Y.; Sajiki, H. Adv. Synth. Catal. 2010, 352, 1630.
(14) (a) Daw, P.; Petakamsetty, R.; Sarbajna, A.; Laha, S.;
Ramapanicker, R.; Bera, J. K. J. Am. Chem. Soc. 2014, 136, 13987.
(b) Tingoli, M.; Mazzella, M.; Panunzi, B.; Tuzi, A. Eur. J. Org.
Chem. 2011, 399. (c) Min, H.; Palani, T.; Park, K.; Hwang, J.; Lee,
S. J. Org. Chem. 2014, 79, 6279. (d) Gao, A.; Yang, F.; Li, J.; Wu, Y.
Tetrahedron 2012, 68, 4950.
(15) Nejatianfar, M.; Akhlaghinia, B.; Jahanshahi, R. Appl. Organomet.
Chem. 2018, 32, e4095; DOI: 10.1002/aoc.4095.
(16) Wang, D.; Li, Z.; Huang, X.; Li, Y. ChemistrySelect 2016, 1, 664.
(17) Rostamnia, S.; Doustkhah, E. Synlett 2015, 26, 1345.
(18) Singh, H.; Rajput, J. K. Appl. Organomet. Chem. 2018, 32, e3989;
DOI: 10.1002/aoc.3989.
(3) Takle, A. K.; Brown, M. J. B.; Davies, S.; Dean, D. K.; Francis, G.;
Gaiba, A.; Hird, A. W.; King, F. D.; Lovell, P. J.; Naylor, A.; Reith, A.
D.; Steadman, J. G.; Wilson, D. M. Bioorg. Med. Chem. Lett. 2006,
16, 378.
(4) Chang, L. L.; Sidler, K. L.; Cascieri, M. A.; de Laszlo, S.; Koch, G.;
Li, B.; MacCoss, M.; Mantlo, N.; O’Keefe, S.; Pang, M.; Rolando,
A.; Hagmann, W. K. Bioorg. Med. Chem. Lett. 2001, 11, 2549.
(5) Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17, 1182.
(6) Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.;
Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y.-H.; Marsh, K.;
Warner, R.; Lee, J. Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg,
S. H.; Sham, H. L. J. Med. Chem. 2002, 45, 1697.
(7) (a) Lindberg, P.; Nordberg, P.; Alminger, T.; Brándstróm, A.;
Wallmark, B. J. Med. Chem. 1986, 29, 1327. (b) Kantevari, S.;
Nair, C. K. S.; Pardhasaradhi, M. J. Heterocycl. Chem. 2006, 43,
1353. (c) Abrahams, S. L.; Hazen, R. J.; Batson, A. G.; Phillips, A.
P. Pharmacol. Exp. Ther. 1989, 249, 359. (d) Wolkenberg, S. E.;
Wisnoski, D. D.; Leister, W. H.; Wang, Y.; Zhao, Z.; Lindsley, C.
W. Org. Lett. 2004, 6, 1453.
(19) Ray, S.; Das, P.; Bhaumik, A.; Dutta, A.; Mukhopadhyay, C. Appl.
Catal., A 2013, 458, 183.
(20) Waheed, M.; Ahmed, N.; Alsharif, M. A.; Alahmdi, M. I.;
Mukhtar, S. ChemistrySelect 2017, 2, 7946.
(8) (a) Magyar, Á.; Hell, Z. Synlett 2019, 30, 89. (b) Higuera, N. L.;
Pena-Solorzano, D.; Ochoa-Puentes, C. Synlett 2019, 30, 225.
(c) Debus, H. Ann. Chem. Pharm. 1858, 107, 199.
(d) Radziszewski, B. Ber. Dtsch. Chem. Ges. 1882, 15, 1493.
(9) (a) Borah, R. K.; Raul, P. K.; Mahanta, A.; Shchukarev, A.;
Mikkola, J.-P.; Thakur, A. J. Synlett 2017, 28, 1177. (b) Garnier,
T.; Sakly, R.; Danel, M.; Chassaing, S.; Pale, P. Synthesis 2017, 49,
1223. (c) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem.
(21) Wan, Y.; Liu, G.; Zhao, L.; Wang, H.; Huang, S.; Chen, L.; Wu, H.
J. Heterocycl. Chem. 2014, 51, 713.
(22) Kalkhorani, N. M.; Heravi, M. M. J. Chem. 2013, Article ID
645801; DOI: 10.1155/2013/645801.
(23) Sadeghi, B.; Mirjalili, B. B. F.; Hashemi, M. M. Tetrahedron Lett.
2008, 49, 2575.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J