Copper-Catalyzed Simultaneous Activation of C-H and N-H Bonds: Three-Component One-Pot Cascade Synthesis of Multi?-substituted Imidazoles

Article abstract of DOI:10.1055/s-0036-1588585

A copper-catalyzed expedient, practical, and straightforward approach for the one-pot three-component modular synthesis of multisubstituted imidazoles has been described by using arylacetic acids, N -arylbenzamidines, and nitroalkanes. The reaction involv

Full text of DOI:10.1055/s-0036-1588585

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–J
paper
A
en
S. D. Pardeshi et al.
Paper
Synthesis
Copper-Catalyzed Simultaneous Activation of C–H and N–H
Bonds: Three-Component One-Pot Cascade Synthesis of Multi-
substituted Imidazoles
Sachin D. Pardeshia§
R1
CuSO4 (10 mol%)
bipy (20 mol%)
Organocatalytic cascade process
Broad substrate scope
Inexpensive catalyst
NH
Pratima A. Sathea
Kamlesh S. Vadagaonkarb§
Lucio Melone*c
N
R3
R1
COOH
R2
N
R2
R4
DMF/R4-CH2-NO2
O2, 130 °C, 8 h
N
R3
H
Formation of C–C and C–N bonds
Atul C. Chaskar*a
a National Centre for Nanosciences and Nanotechnology,
University of Mumbai, Vidyanagari, Kalina Campus,
Santacruz (East), Mumbai-400098, India
achaskar25@gmail.com
b Department of Dyestuff Technology, Institute of Chemical
Technology, Nathalal Parekh Marg, Matunga (East),
Mumbai-400019, India
c Dipartimento di Chimica, Materiali ed Ingegneria Chimica,
‘G. Natta’, Politecnico Di Milano, via L. Mancinelli, 7, 20131
Milano, Italy
lucio.melone@polimi.it
§ Authors contributed equally to this work.
Received: 11.09.2017
Accepted after revision: 12.09.2017
Published online: 10.10.2017
their multiple bond breaking and bond forming ability
within a single step. A steady growth in their development
bears witness to their usability.
DOI: 10.1055/s-0036-1588585; Art ID: ss-2017-z0357-op
Imidazole is a widely explored nitrogen heterocycle ow-
ing to its existence in many natural products3 and pharma-
ceutical compounds.4 Imidazole derivatives are known to
exhibit a wide range of medicinal properties,5 such as anti-
fungal,6 antitumor,7 antibacterial,8 antiplasmodium,9 and
anti-inflammatory.10 Furthermore, they are also key con-
stituents of numerous functional materials,11 such as or-
ganic semiconductors,12 dyes,13 optoelectronic materials,14
etc. In addition to this, imidazole salts are considered as ele-
gant materials due to their liquid nature at room tempera-
ture and have been extensively used as catalysts and/or
green reaction media as well as electrolytes for solar cells
and batteries. These significant potential applications have
led to the development of various methods for the synthesis
of imidazole scaffolds with wide substitution patterns. Be-
side the classical and simple one-pot synthesis of imida-
zoles by using 1,2-diketones/α-hydroxy ketones/α-halo ke-
tones/α-amino ketones, primary amine, an aldehyde, and
ammonium acetate, several novel protocols, such as aldi-
mine cross-coupling,15 catalyst-free domino reaction of 2-
azido acrylates and nitrones,16 cycloaddition of amidines
and nitroolefins,17 the three-component reaction,18 Ni-cata-
lyzed dehydrogenation of benzylic-type imines,19 and Zn-
catalyzed cyclization of 2-(tetrazol-5-yl)-2H-azirines and
imines,20 have been reported. Moreover, Chiba and Chen
synthesized imidazole from oximes by using copper(I) io-
dide and K3PO4.21 Mirzaei and co-workers also reported the
synthesis of N-substituted 2,4-diarylimidazoles via a multi-
Abstract A copper-catalyzed expedient, practical, and straightforward
approach for the one-pot three-component modular synthesis of multi-
substituted imidazoles has been described by using arylacetic acids, N-
arylbenzamidines, and nitroalkanes. The reaction involves simultaneous
activation of C–H and N–H bonds of arylacetic acids and N-arylbenz-
amidines, respectively. The use of inexpensive copper sulfate as a cata-
lyst, readily available starting materials, and Celite-free workup makes
this protocol economically viable. Multisubstituted imidazoles were ob-
tained in moderate to good yields with significant functional group tol-
erance and high regioselectivity.
Key words arylacetic acid, N-arylbenzamidine, C–H bond activation,
N–H bond activation, CuSO4, imidazole
In recent years, C–H functionalization has become a
widely admired, elegant tool in organic synthesis due to se-
lective construction of new bonds and rapid assembly of
complex molecular framework from easily available simple
starting materials. The mechanistic understanding of C–H
functionalization has enabled extensive efforts for carbon–
carbon and carbon–heteroatom bonds formation which has
prompted the development of innovative synthetic strate-
gies.1,2 Obviously, identifying a specific method is always a
crucial starting point. Among various transition elements,
copper has extensively been employed for C–H functional-
ization due to its variable oxidation states. Indeed, multi-
component-based target-oriented cascade strategies pro-
vided an efficient entry to nitrogen heterocycles owing to
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

B
S. D. Pardeshi et al.
Paper
Synthesis
component reaction,22 while Meille and co-workers synthe-
sized imidazoles through FeCl3-mediated ring opening of
2H-azirines.23
Table 1 Optimization of the Reaction Conditionsa
H
N
Amidines have been widely employed synthetic precur-
sors due to their easy availability and ability to furnish mul-
tisubstituted imidazoles via [3+2] cycloaddition reaction or
radical pathway. In this context, Chen and co-workers re-
ported the synthesis of trisubstituted imidazoles from ace-
tophenones24 by using a combination of I2 with zinc iodide
as catalysts, whereas Mandal and co-workers25 synthesized
imidazoles from phenacyl bromide by using KHCO3 as a
base. An iron-catalyzed protocol was established for alde-
hydes18c while [3+2] cycloaddition of nitrovinylbenzene
was accomplished by using copper(I) iodide.17a Moreover,
Neuville and Li have described the synthesis of trisubstitut-
ed imidazoles from phenylacetylene by using copper chlo-
ride as a catalyst over a period of 24 hours26 while Mahajan
and co-workers used nitrosovinylbenzene in dichlorometh-
ane to form imidazoles.27 1,3-Dicarbonyl compounds, ke-
tones, and chalcones are successfully used along with ami-
dines for the synthesis of imidazoles.28
Despite the proven useful track record of previously re-
ported methods, the requirements for functionalized sub-
strates, high catalyst loading, long reaction times, and low
yields of products limit their wider applicability. Indeed,
our interest in metal-catalyzed C–H functionalization me-
diated tandem synthesis of N-heterocycles29 has led us to
the one-pot, three-component synthesis of multisubstitut-
ed imidazoles using arylacetic acids, N-arylbenzamidines,
and nitroalkanes under aerobic oxidative conditions
through simultaneous C–H and N–H bond activation. An
easy sp3 C–H bond activation followed by decarboxylation
under mild reaction conditions is the key factor behind the
selection of arylacetic acids.
We anticipated phenylacetic acid (1a) as the most suit-
able starting arylacetic acid for fine-tuning the reaction pa-
rameters to accomplish highest yield of imidazole scaffold.
When the reaction of phenylacetic acid (1a, 1.5 equiv) with
N-phenylbenzamidine (2a, 1.0 equiv) was performed in the
presence of 5 mol% of CuSO4 as a catalyst in DMF/CH3NO2
solvent system under an oxygen atmosphere at 130 °C, the
desired 1,2,4-triphenyl-1H-imidazole (3aa) was isolated in
only 10% yield, but the yield was enhanced to 20% when
catalyst loading was increased to 10 mol% (Table 1, entry 1).
Nitromethane acted as a single carbon synthon. We were
delighted to find a great increase in the yield when 2,2′-bi-
pyridyl (bipy) was used as a ligand along with 10 mol% of
CuSO4 (entry 2), this could be attributed to the stabilization
of Cu2+ species by the 2,2′-bipyridyl ligand. This encourag-
ing result prompted us to focus our attention on screening
different parameters encompassing temperature, catalyst
and ligand loading, substrate concentration, and solvent
system in order to explore the optimal reaction conditions.
The detrimental role of temperature and concentration of
N
H
catalyst, ligand
N
COOH
solvent, 130 °C
O2, 8 h
N
1a
3aa
2a
Entry Catalyst (mol%) Ligand (mol%)
Solvent
Yield
(%)b
1
2
3
CuSO4 (10)
CuSO4 (5)
–
DMF/CH3NO2
DMF/CH3NO2
DMF/CH3NO2
20
10
CuSO4 (10)
bipy (20)
bipy (10)
80
60
CuSO4 (10)
bipy (20)
80
50c
44d
20e
4
CuSO4 (10)
bipy (20)
DMF/CH3NO2
60f
20g
5h
6
CuSO4 (10)
CuI (10)
bipy (20)
bipy (20)
bipy (20)
bipy (20)
bipy (20)
bipy (20)
bipy (20)
o-Phen (20)
Ph3P (20)
DMF/CH3NO2
DMF/CH3NO2
DMF/CH3NO2
DMF/CH3NO2
DMF/CH3NO2
DMF/CH3NO2
DMF/CH3NO2
DMF/CH3NO2
DMF/CH3NO2
n.r.
25
32
40
28
43
54
37
23
31
7
CuCl (10)
8
CuCl2 (10)
CuBr (10)
9
10
CuBr2 (10)
Cu(OAc)2 (10)
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
11
12
13
14
8-hydroxyquinoline DMF/CH3NO2
(20)
15
16
17
18
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
bipy (20)
bipy (20)
bipy (20)
bipy (20)
DMF/CH3NO2
49
41
1,2-DCE/CH3NO2
1,4-dioxane/CH3NO2 55
DMI/CH3NO2 52
a Reaction conditions: phenylacetic acid (1a, 1.5 mmol), N-phenylbenzami-
dine (1b, 1.0 mmol), catalyst (10 mol%), ligand (20 mol%), solvent (2.0 mL),
130 °C, 8 h, under O2 atmosphere.
b Yield of isolated product after column chromatography.
c Reaction performed at 120 °C.
d Reaction performed at 110 °C.
e Reaction performed at 90 °C.
f Phenylacetic acid (1.0 mmol).
g Phenylacetic acid (0.5 mmol).
h Reaction performed under N2 atmosphere or argon atmosphere.
phenylacetic acid was noticed as the yield of imidazole di-
minished with lower temperature (entry 3) as well as con-
centration of phenylacetic acid (entry 4). Notably, no reac-
tion occurred under nitrogen or argon atmosphere (entry
5). Various copper catalysts were tested, but they failed to
provide an improved outcome (entries 6–11). Various
ligands were also screened under standard conditions,
however, they gave lower yields of 3aa when compared to
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S. D. Pardeshi et al.
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Synthesis
2,2′-bipyridyl (entries 12–14). Moreover, different solvent
systems, DMSO/CH3NO2, 1,2-DCE/CH3NO2, 1,4-dioxane/CH3NO2,
1,3-dimethylimidazolidin-2-one (DMI)/CH3NO2, were also
screened, but unfortunately lower yields of the product
were observed (entries 15–18). All these observations im-
plied that the best conditions are: phenylacetic acid (1a, 1.5
equiv), N-phenylbenzamidine (2a, 1.0 equiv), CuSO4
(10 mol%), 2,2′-bipyridyl (bipy, 20 mol%), DMF/CH3NO2, 130 °C,
under oxygen. A Celite-free workup, unlike FeCl3-catalyzed
reactions, leads to enhancement of the yield which appar-
ently demonstrates the potential applicability of this proto-
col for large-scale synthesis.
stitution pattern is mandatory for the wider acceptability of
process. At the outset, diverse arylacetic acids 1a–i were
screened under the optimized conditions and it was found
that nature of the substituents govern the yield of the prod-
uct (Scheme 1). N-Phenylbenzamidine (2a) on reaction
with phenylacetic acid (1a) afforded 1,2,4-triphenyl-1H-
imidazole (3aa) in 80% yield. 3-Chloro- 1b and 4-bromo-
substituted phenylacetic acid 1c gave imidazoles 3ba and
3ca in moderate yields. Notably, 4-methyl- 1d and 4-meth-
H
CuSO4 (10 mol%)
bpy (20 mol%)
N
N
With these optimized conditions in hand, we evaluated
the substrate scope of this method by using various aryl-
acetic acids, N-arylbenzamidines, and nitroalkanes as gen-
eralization with respect to different substituents and sub-
H
R2
COOH
R2
N
R3
N
DMF/CH3NO2, 130 °C
O2, 8 h
R3
2
3
1a
R2 = 3-ClC6H4, 4-ClC6H4, 3-MeC6H4, 4-MeC6H4, 4-MeOC6H4
R3 = 2-FC6H4, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4
R1
H
N
N
CuSO4 (10 mol%)
bpy (20 mol%)
H
N
N
R1
COOH
N
N
N
DMF/CH3NO2, 130 °C
O2, 8 h
N
N
N
Cl
2a
3
1
Cl
R1 = Ph, 3-ClC6H4, 4-BrC6H4, 4-MeC6H4, 4-MeOC6H4, 4-NCC6H4,
naphthalen-1-yl, naphthalen-2-yl, thiophen-2-yl
3ac (65%)
3ab (52%)
3ad (71%)
Br
Cl
N
N
N
N
N
N
N
N
N
N
N
N
MeO
F
3af (75%)
3ag (45%)
3ae (73%)
3ca (60%)
3ba (54%)
3aa (80%)
OMe
CN
N
N
N
N
N
N
N
N
N
N
N
N
Cl
Cl
Cl
3aj (62%)
3ah (48%)
3ai (56%)
3da (70%)
3fa (69%)
3ea (71%)
S
N
N
N
N
N
N
N
N
N
N
Me
OMe
3ga (51%)
3ia (45%)
3ak (72%)
3al (77%)
3ha (47%)
Scheme 2 Scope of various N-substituted amidines in the copper-
catalyzed synthesis of imidazoles. Reagents and conditions: phenylacetic
acid (1a, 1.5 mmol), N-arylbenzamidine 2 (1.0 mmol), CuSO4
(10 mol%), 2,2′-bipyridyl (20 mol%), DMF/CH3NO2 (1.5:0.5 mL), 130 °C,
8 h, O2 atmosphere; isolated yields are given.
Scheme 1 Scope of various arylacetic acids in the copper-catalyzed
synthesis of imidazoles. Reagents and conditions: arylacetic acid 1
(1.5 mmol), N-phenylbenzamidine (2a, 1.0 mmol), CuSO4 (10 mol%),
2,2′-bipyridyl (20 mol%), DMF/CH3NO2 (1.5:0.5 mL), 130 °C, 8 h, under
O2 atmosphere; isolated yields are given.
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S. D. Pardeshi et al.
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oxy-substituted arylacetic acid 1e gave the corresponding
imidazoles 3da and 3ea in 70% and 71% yields, respectively.
Arylacetic acid 1f bearing an electron-withdrawing 4-CN
group gave desired imidazole 3fa in 69% yield. Along with
this we further screened naphthalene-1-acetic acid (1g)
and naphthalene-2-acetic acid (1h) which furnished prod-
uct 3ga and 3ha with moderate yields 51% and 47%, respec-
tively. Moreover, we carried out the reaction of heterocyclic
acetic acid, thiophene-2-acetic acid (1i) with N-phenylbenz-
amidine (2a) resulting in product 3ia in 45% yield.
Furthermore, we assessed the use of various N-aryl-
benzamidines 2a–l bearing substituents of varying elec-
tronic character and steric effect on both the phenyl rings
with phenylacetic acid (1a) (Scheme 2). Indeed, N-phenyl-
benzamidines bearing halogen substituents (3-Cl 2b and
4-Cl 2c) as well as electron-donating substituents (3-Me 2d,
4-Me 2e, and 4-OMe 2f) gave imidazoles 3ab–af in moder-
ate to good yields (52–75%). However, an N-phenylbenz-
amidine bearing NO2 group (not shown) did not react with
phenylacetic acid under the same reaction conditions. Simi-
larly, the effects of the substituents on the N-phenyl ring of
the N-arylbenzamidine were also investigated. A moderate
yields (45–62%) of imidazoles 3ag–aj were observed for N-
arylbenzamidines bearing halogen substituents (2-F 2g,
2-Cl 2h, 3-Cl 2i, and 4-Cl 2j). N-Arylbenzamidines bearing
electron-donating substituents (4-Me 2k and 4-OMe 2l)
gave the corresponding imidazoles 3ak and 3al in 72% and
77% yields. No product formation was observed for N-aryl-
benzamidines bearing a NO2 substituent.
Encouraged by these results, we next turned our atten-
tion to the synthesis of disubstituted and tetrasubstituted
imidazoles by exploring the use of benzamidine and nitro-
ethane, respectively (Scheme 3). The use of arylacetic acids
bearing electron-donating (4-Me 1d and 4-OMe 1e) substit-
uents with benzamidine (4) afforded respective disubsti-
tuted imidazoles 5a and 5b in 74% and 76% yields, respec-
tively. An arylacetic acid 1j with an electron-withdrawing
(3-CF3) substituent with benzamidine (4) produced corre-
sponding disubstituted imidazoles 5c in 68% yield. N-
Phenylbenzamidine (2a) bearing an electron donating (2-Me)
group on reaction with phenylacetic acid (1a) in the pres-
ence of DMF/nitroethane solvent system afforded tetra-
substituted imidazole 5d in 65% yield.
To gain insight on the role of CuII(Ln) and endorse our
hypothesis, a few controlled experiments were conducted.
Initially, when a mixture of phenylacetic acid (1a), CuSO4,
and 2,2′-bipyridyl was heated in DMF at 130 °C for 2 hours
under an O2 atmosphere, 95% conversion into benzaldehyde
(A) was observed [Scheme 4 (a)]. The same reaction failed
to give benzaldehyde (A) in the presence of radical inhibitor
TEMPO [Scheme 4 (b)]. This clearly indicated that reaction
O
CuSO4 (10 mol%)
bipy (20 mol%)
H
(a)
COOH
COOH
DMF, 130 °C, O2, 2 h
R1
A (95% conversion)
1a
1a
NH
CuSO4 (10 mol%)
bpy (20 mol%)
N
R1
COOH
R2
NH
R3
R4
O
H
R2
CuSO4 (10 mol%)
bipy (20 mol%)
N
R3
DMF/R4CH2NO2, 130 °C
O2, 8 h
(b)
TEMPO, DMF, 130 °C
O2, 2 h
2 or 4
5
1
A (0%)
R1 = 4-BrC6H4, 4-MeC6H4, 3-F3CC6H4; R2 = Ph, 2-MeC6H4; R3 = H, Ph; R4 = H, CH3
OMe
COOH
CuSO4 (10 mol%)
bipy (20 mol%)
N
N
N
N
1a
(c)
N
N
TEMPO, DMF/CH3NO2
130 °C, O2, 8 h
H
H
NH
5b (76%)
5a (74%)
N
H
3aa (0%)
2a
CF3
N
O
N
N
COOH
N
H
CuSO4 (10 mol%)
bipy (20 mol%)
6
N
N
(d)
5c (68%)
5d (65%)
DMF/CH3NO2, 130 °C
O2, 8 h
NH
Scheme 3 Scope of benzamidines and nitroethane in the copper-
catalyzed synthesis of imidazoles. Reagents and conditions: arylacetic
acid 1 (1.5 mmol), N-arylbenzamidine 2 or benzamidine 4 (1.0 mmol),
CuSO4 (10 mol%), 2,2′-bipyridyl (20 mol%), DMF/CH3NO2 or DMF/EtNO2
(2 mL), 130 °C, 8 h, O2 atmosphere; isolated yields are given.
N
H
3aa (75%)
2a
Scheme 4 Control experiments
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Synthesis
has proceeded by following single electron transfer (SET)
pathway owing to CuII(Ln). Similarly no product was ob-
served when CuII(Ln)-catalyzed reaction of phenylacetic
acid (1a) and N-phenylbenzamidine (2a) was carried out in
the presence of TEMPO [Scheme 4 (c)]. In order to confirm
that the reaction proceeds through the formation of an α-
keto acid, we carried out the reaction of α-keto acid 6 with
N-phenylbenzamidine (2a) under the optimized reaction
conditions [Scheme 4 (d)] and found that the reaction pro-
duced imidazole 3aa in 75% yield, thereby indicating the
formation of an α-keto acid as an intermediate in this reac-
tion.
A plausible mechanism, developed from these results
and the literature reports, is depicted in Scheme 5. Initially,
CuII(Ln) E catalyzed C–H activation of arylacetic acid 1 oc-
curs in the presence of oxygen via peroxide linkage forma-
tion to afford α-keto acid,30,31 which on oxidative decarbox-
ylation gives aromatic aldehyde A. Further, N-arylbenzami-
dine 2 in the presence of CuII(Ln) E undergoes auto-
oxidation to generate a stable biradical via N–H activa-
tion.17a,32 This, on nucleophilic substitution reaction with
aromatic aldehyde, yields intermediate B. Then nitroalkane
(Michael donor) undergoes regioselective Michael addi-
tion33,34 with intermediate B to form basic skeleton C which
forms thermodynamically stable intermediate having a
five-membered ring D. The stereoelectronic effect of C
drives radical 5-exo-trig cyclization35 due to better orbital
overlapping to give intermediate D, which in the presence
of CuII(Ln) E complex undergoes β-hydride elimination to
give substituted imidazole 3 as the desired product with
the liberation of nitroxyl gas.
We have developed a copper-catalyzed efficient proto-
col for the synthesis of multisubstituted imidazoles via
simultaneously C–H and N–H activation of easily available
arylacetic acids and N-arylbenzamidines. Also we report
phenylacetic acid as an alternative to benzaldehyde since it
offer advantages like wide substrate scope, stable and ro-
bust nature, etc. We strongly believe that this method will
open a new avenue for the synthesis of biologically import-
ant multisubstituted imidazoles and should find broad ap-
plication in modern synthetic chemistry as well as medici-
nal chemistry.
N-Arylbenzamidines were synthesized according to a literature pro-
cedure.36 Chemical reagents were purchased from commercial suppli-
ers. All the solvents were purchased from Spectrochem and were
used as received. DMF was dried by using vacuum distillation and was
stored over 4–Å molecular sieves before use. All reactions were per-
formed in a round-bottom flask and monitored by TLC performed on
aluminum plates (0.25 mm, E. Merck) precoated with silica gel (Merck
CuSO4
H
H
R1
COOH
Ln
C–H Activation
CO2
1
CuII(Ln)
Cu2+
R2
R3
CuII(Ln)
O
N
N
Cu1+
O2
R1
R4
R1
H
A
R2
3
R3
HN
N
HNO
H
β-Hydride
Elimination
2
CuII(Ln)
H2O
N–H Activation
R2
R3
R2
N
N
R4
H
R3
N
N
R1
N
R1
O
H
OCuII(Ln)
R4
H
CuII(Ln)
D
O2N
R2
B
5-exo-trig
Cyclization
R3
H
N
R4
N
Michael Addition
2+
R1
OCuII(Ln)
N
CuII(Ln)
N
N
O
N
=
2–
SO4
Cu
C
N
E
Scheme 5 Proposed reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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S. D. Pardeshi et al.
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Synthesis
60 F-254). Developed TLC plates were visualized under a short-wave-
length UV lamp. Reactions were conducted under open air and O2 at-
mosphere. Yields refer to spectroscopically (1H, 13C NMR) homo-
geneous material obtained after column chromatography performed
on silica gel (230–400 mesh) supplied by Avra laboratories, India.
Petroleum ether = PE. 1H and 13C NMR were recorded in CDCl3 on a
Bruker 400 and 300 MHz spectrometer relative to TMS (δ = 0.0) as an
internal standard. High-resolution mass spectra (HRMS) were ob-
tained by using positive electrospray ionization (ESI) and the time-of-
flight (TOF) method. Melting points were recorded on a standard
melting point apparatus from Sunder Industrial Product, Mumbai and
are uncorrected.
1,2-Diphenyl-4-(p-tolyl)-1H-imidazole (3da)24
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 107 mg (70%).
1H NMR (300 MHz, CDCl3): δ = 7.91–7.88 (m, 2 H), 7.49–7.46 (m, 2 H),
7.42–7.37 (m, 3 H), 7.29–7.24 (m, 4 H), 7.21 (s, 1 H), 7.18 (s, 1 H),
7.16–7.12 (m, 2 H), 2.39 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 146.9, 141.8, 138.6, 136.7, 131.1, 130.4,
129.5, 129.3, 128.8, 128.4, 128.2, 128.1, 125.9, 125.0, 118.1, 21.3.
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.1548; found:
311.1545.
4-(4-Methoxyphenyl)-1,2-diphenyl-1H-imidazole (3ea)18c
Multisubstituted Imidazoles 3 and 5; General Procedure
Purified by column chromatography (EtOAc/PE 1:9) as a light yellow
oil; yield: 109 mg (71%).
1H NMR (400 MHz, CDCl3): δ = 7.84–7.81 (distorted t, J = 3.2, 2.0 Hz, 2
H), 7.46–7.44 (m, 2 H), 7.39–7.35 (m, 4 H), 7.28–7.23 (m, 5 H), 6.97–
6.93 (tt, J = 3.2, 2.0 Hz, 2 H), 3.82 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.9, 146.9, 141.6, 138.6, 134.3,
131.8, 129.6, 128.5, 128.3, 126.4, 125.9, 124.6, 120.5, 117.7, 114.1,
55.4.
A round-bottom flask was charged with arylacetic acid 1 (1.5 mmol),
N-arylbenzamidine 2 or 4 (1.0 mmol), CuSO4 (10 mol%), and 2,2′-bi-
pyridyl (20 mol%). A pre-oxygen degassed solvent system of DMF/ni-
troalkane (1.5:0.5 mL) was added to above mixture. The resulting
mixture was heated at 130 °C for 8 h. The reaction progress was mon-
itored by using TLC. After completion of the reaction, water was add-
ed to the mixture and the aqueous layer was extracted with EtOAc.
The combined organic layers were dried (anhyd Na2SO4) and concen-
trated under reduced pressure. The residue was purified by flash col-
umn chromatography (230–400 mesh silica gel, EtOAc/n-hexane) to
afford imidazoles 3 or 5.
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O: 327.1497; found:
327.1499.
4-(1,2-Diphenyl-1H-imidazol-4-yl)benzonitrile (3fa)18c
1,2,4-Triphenyl-1H-imidazole (3aa)18c
Purified by column chromatography (EtOAc/PE 1:9) as a pale yellow
solid; yield: 106 mg (69%); mp 198–200 °C.
1H NMR (400 MHz, CDCl3): δ = 7.89–7.88 (m, 1 H), 7.86 (d, J = 4.0 Hz, 1
H), 7.66 (d, J = 1.2 Hz, 1 H), 7.64 (s, 1 H), 7.56 (t, J = 4 Hz, 1 H), 7.54 (t,
J = 1.6 Hz, 1 H), 7.52–7.47 (m, 4 H), 7.40 (t, J = 1.6 Hz, 1 H), 7.38 (s, 1
H), 7.36 (t, J = 1.6 Hz, 1 H), 7.18–7.14 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 145.9, 142.0, 138.3, 133.7, 131.5,
130.3, 129.8, 129.3, 128.7, 128.6, 127.2, 125.9, 125.1, 122.9, 120.0,
118.9.
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 120 mg (80%).
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8 Hz, 2 H), 7.47–7.45 (m, 3
H), 7.43–7.39 (m, 5 H), 7.33 (s, 1 H), 7.28–7.24 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 147.4, 142.1, 138.8, 134.2, 130.6,
129.9, 129.2, 129.0, 128.9, 128.6, 127.4, 126.4, 126.2, 125.5, 118.9.
HRMS (ESI): m/z [M + H]+ calcd for C21H17N2: 297.1392; found:
297.1390.
HRMS (ESI): m/z [M + H]+ calcd for C22H16N3: 322.1344; found:
322.1347.
4-(3-Chlorophenyl)-1,2-diphenyl-1H-imidazole (3ba)
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 83 mg (54%).
4-(Naphthalen-1-yl)-1,2-diphenyl-1H-imidazole (3ga)
Purified by column chromatography (EtOAc/PE 3:7) as a yellow oil;
yield: 79 mg (51%).
1H NMR (300 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.74–7.71 (m, 3 H), 7.51
(d, J = 7.5 Hz, 3 H), 7.46–7.37 (m, 4 H), 7.32 (t, J = 7.5 Hz, 3 H), 7.22 (d,
J = 8.1 Hz, 2 H), 7.15 (s, 1 H), 7.04 (t, J = 7.5 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 347.1548; found:
347.1550.
1H NMR (400 MHz, CDCl3): δ = 7.90–7.87 (m, 1 H), 7.75–7.73 (m, 1 H),
7.47–7.38 (m, 6 H), 7.31–7.21 (m, 7 H).
13C NMR (100 MHz, CDCl3): δ = 140.5, 138.3, 135.7, 134.7, 130.0,
129.6, 128.9, 128.7, 128.4, 128.4, 128.4, 128.3, 127.0, 125.9, 125.2,
123.1, 119.1.
HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found:
331.1005.
4-(Naphthalen-2-yl)-1,2-diphenyl-1H-imidazole (3ha)
4-(4-Bromophenyl)-1,2-diphenyl-1H-imidazole (3ca)23
Purified by column chromatography (EtOAc/PE 3:7) as a yellow oil;
yield: 73 mg (47%).
1H NMR (300 MHz, CDCl3): δ = 8.03 (s, 1 H), 7.80–7.82 (m, 4 H), 7.63
(d, J = 7.8 Hz, 3 H), 7.51 (t, J = 2.7 Hz, 1 H), 7.48 (t, J = 1.2 Hz, 1 H),
7.45–7.40 (m, 3 H), 7.34 (t, J = 8.1 Hz, 3 H), 7.13 (t, J = 7.5 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 347.1548; found:
347.1546.
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 95 mg (60%).
1H NMR (300 MHz, CDCl3): δ = 7.79–7.74 (tt, J = 3 Hz, 2 H), 7.54–7.49
(tt, J = 3 Hz, 2 H), 7.46–7.39 (m, 6 H), 7.28–7.24 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 147.7, 141.8, 136.4, 133.8, 131.8, 130.7,
130.2, 129.4, 128.6, 128.3, 128.1, 127.8, 127.0, 125.1, 118.5.
HRMS (ESI): m/z [M + H]+ calcd for C21H16BrN2: 375.0497; found:
375.0495.
1,2-Diphenyl-4-(thiophen-2-yl)-1H-imidazole (3ia)
Purified by column chromatography (EtOAc/PE 4:6) as a yellow oil;
yield: 70 mg (45%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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1H NMR (300 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.86 (d, J = 6.9 Hz, 2 H),
7.64 (t, J = 7.8 Hz, 3 H), 7.53–7.43 (m, 4 H), 7.35 (t, J = 8.1 Hz, 3 H), 7.14
(t, J = 7.5 Hz, 1 H).
1H NMR (300 MHz, CDCl3): δ = 7.84–7.80 (distorted t, J = 2.1, 1.5 Hz, 3
H), 7.64 (d, J = 5.7 Hz, 1 H), 7.44–7.36 (m, 5 H), 7.26–7.22 (m, 4 H),
6.96–6.92 (distorted tt, J = 2.1, 1.5 Hz, 2 H ), 3.81 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H15N2S: 303.0950; found:
303.0958.
13C NMR (100 MHz, CDCl3): δ = 158.9, 146.9, 141.6, 138.6, 131.8,
129.6, 128.9, 128.3, 128.2, 127.2, 126.4, 125.9, 124.6, 117.7, 114.1,
55.4.
2-(3-Chlorophenyl)-1,4-diphenyl-1H-imidazole (3ab)23
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O: 327.1497; found:
327.1494.
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 80 mg (52%).
1H NMR (400 MHz, CDCl3): δ = 7.87–7.84 (m, 2 H), 7.55 (t, J = 2.0 Hz, 1
H), 7.43–7.41 (m, 4 H), 7.39–7.36 (m, 2 H), 7.27–7.24 (m, 3 H), 7.18 (t,
J = 1.6 Hz, 1 H), 7.15 (s, 1 H), 7.13 (s, 1 H).
1-(2-Fluorophenyl)-2,4-diphenyl-1H-imidazole (3ag)
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 69 mg (45%).
13C NMR (100 MHz, CDCl3): δ = 145.5, 142.0, 138.2, 134.4, 133.7,
132.0, 129.7, 129.4, 128.9, 128.8, 128.6, 128.6, 127.3, 126.8, 125.9,
125.1, 119.0.
HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found:
331.0998.
1H NMR (400 MHz, CDCl3): δ = 7.91–7.89 (m, 1 H), 7.76–7.74 (tt, J =
1.2 Hz, 1 H), 7.45–7.37 (m, 7 H), 7.29–7.24 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 147.4, 142.0, 138.8, 134.2, 134.1,
130.6, 129.9, 129.2, 129.0, 128.9, 128.7, 128.6, 127.4, 126.4, 126.2,
125.5, 118.9.
HRMS (ESI): m/z [M + H]+ calcd for C21H16FN2: 315.1298; found:
315.1301.
2-(4-Chlorophenyl)-1,4-diphenyl-1H-imidazole (3ac)37
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 100 mg (65%).
1-(2-Chlorophenyl)-2,4-diphenyl-1H-imidazole (3ah)
1H NMR (400 MHz, CDCl3): δ = 7.88–7.85 (m, 2 H), 7.45–7.38 (m, 8 H),
7.33 (t, J = 2.0 Hz, 1 H), 7.31–7.29 (m, 1 H), 7.27–7.25 (m, 2 H), 7.24 (s,
1 H).
13C NMR (75 MHz, CDCl3): δ = 145.9, 142.0, 138.3, 133.7, 131.5, 130.3,
129.8, 129.3, 128.7, 128.6, 127.2, 125.9, 125.1, 122.9, 118.9.
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 74 mg (48%).
1H NMR (400 MHz, CDCl3): δ = 7.89–7.86 (m, 2 H), 7.44 (s, 2 H), 7.39
(d, J = 7.6 Hz, 2 H), 7.36 (distorted t, J = 2.0, 1.2 Hz, 1 H), 7.34–7.28 (m,
6 H), 7.25 (s, 1 H), 7.11–7.09 (distorted tt, J = 1.6, 1.2 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found:
331.0999.
13C NMR (100 MHz, CDCl3): δ = 146.9, 141.9, 139.4, 135.0, 133.4,
131.4, 130.4, 129.8, 128.8, 128.7, 128.6, 128.3, 127.1, 125.8, 125.0,
124.1, 118.1.
1,4-Diphenyl-2-(m-tolyl)-1H-imidazole (3ad)37
HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found:
331.1005.
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 108 mg (71%).
1-(3-Chlorophenyl)-2,4-diphenyl-1H-imidazole (3ai)37
1H NMR (300 MHz, CDCl3): δ = 7.89–7.86 (m, 2 H), 7.43–7.37 (m, 6 H),
7.33 (d, J = 6.0 Hz, 2 H), 7.28–7.26 (m, 2 H), 7.24 (s, 1 H), 7.06 (d, J = 6.0
Hz, 2 H), 2.31 (s, 3 H).
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 86 mg (56%).
13C NMR (100 MHz, CDCl3): δ = 147.2, 141.6, 138.7, 138.5, 134.0,
129.6, 129.5, 129.3, 129.0, 128.8, 128.7, 128.2, 127.5, 127.0, 125.9,
125.1, 118.4, 21.4.
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.1548; found:
311.1545.
1H NMR (400 MHz, CDCl3): δ = 7.89–7.86 (m, 2 H), 7.46–7.35 (m, 6 H),
7.33–7.25 (m, 6 H), 7.11–7.08 (distorted tt, J = 1.6, 1.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 147.3, 142.0, 138.8, 134.4, 133.6,
130.6, 129.9, 129.2, 129.0, 128.9, 128.7, 128.6, 127.4, 126.4, 126.2,
125.5, 118.9.
HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found:
331.0997.
1,4-Diphenyl-2-(p-tolyl)-1H-imidazole (3ae)17b
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 110 mg (73%).
1-(4-Chlorophenyl)-2,4-diphenyl-1H-imidazole (3aj)24
1H NMR (400 MHz, CDCl3): δ = 7.89–7.87 (m, 2 H), 7.43–7.35 (m, 7 H),
7.34 (t, J = 2.0 Hz, 1 H), 7.32 (t, J = 2.0 Hz, 1 H), 7.28–7.25 (m, 3 H), 7.24
(s, 1 H), 2.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 147.3, 141.6, 138.7, 138.5, 134.0,
129.5, 129.0, 128.8, 128.7, 128.2, 127.5, 127.0, 125.9, 125.1, 118.4,
21.4.
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 95 mg (62%).
1H NMR (300 MHz, CDCl3): δ = 7.93–7.89 (m, 2 H), 7.54–7.51 (tt, J =
0.9 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.41–7.36 (m, 5 H), 7.34–7.32 (m, 2
H), 7.27–7.24 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 147.7, 141.8, 136.4, 133.8, 131.8, 130.7,
130.2, 129.4, 128.6, 128.3, 128.1, 127.8, 127.0, 125.1, 118.5.
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.1548; found:
311.1549.
HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found:
331.1004.
2-(4-Methoxyphenyl)-1,4-diphenyl-1H-imidazole (3af)37
Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil;
yield: 116 mg (75%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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2,4-Diphenyl-1-(p-tolyl)-1H-imidazole (3ak)18c
5-Methyl-1,4-diphenyl-2-(o-tolyl)-1H-imidazole (5d)
Purified by column chromatography (EtOAc/PE 1:9) as a light yellow
oil; yield: 110 mg (72%).
Purified by column chromatography (EtOAc/PE 1:9) as a colorless oil;
yield: 103mg (65%).
1H NMR (300 MHz, CDCl3): δ = 7.91–7.88 (m, 2 H), 7.49–7.46 (m, 2 H),
7.42–7.37 (m, 3 H), 7.29–7.25 (m, 4 H), 7.21 (s, 1 H), 7.18 (s, 1 H),
7.16–7.12 (m, 2 H), 2.39 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 7.6 Hz, 2 H), 7.47 (distorted
t, J = 8.1, 7.3 Hz, 5 H), 7.33 (distorted t, J = 8.0, 5.6 Hz, 3 H), 7.24–7.22
(m, 2 H), 7.03 (d, J = 8.0 Hz, 2 H), 2.29 (s, 3 H), 2.28 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 147.0, 141.5, 138.2, 136.0, 133.8, 130.3,
130.1, 128.8, 128.6, 128.4, 128.2, 127.0, 125.6, 125.1, 118.7, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.1548; found:
311.1552.
13C NMR (100 MHz, CDCl3): δ = 146.4, 138.0, 137.4, 135.0, 132.2,
129.7, 129.5, 129.2, 129.0, 128.9, 128.8, 128.7, 128.5, 128.4, 126.5,
126.1.
HRMS (ESI): m/z [M + H]+calcd for C23H21N2: 325.1699; found:
325.1701.
1-(4-Methoxyphenyl)-2,4-diphenyl-1H-imidazole (3al)17b
Purified by column chromatography (EtOAc/PE 1:9) as a light yellow
oil; yield: 118 mg (77%).
Acknowledgment
1H NMR (400 MHz, CDCl3): δ = 7.90–7.87 (m, 2 H), 7.49–7.45 (m, 2 H),
7.42–7.37 (m, 3 H), 7.27–7.23 (m, 4 H), 7.20–7.15 (distorted tt, J = 4.4,
2.8 Hz, 2 H), 6.92–6.87 (distorted tt, J = 4.4, 2.8 Hz, 2 H), 3.82 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.3, 147.1, 141.9, 134.0, 131.5, 130.4,
128.7, 128.6, 128.3, 128.2, 127.1, 126.9, 125.0, 118.9, 114.6, 55.5.
S.D.P thanks Department of Science and Technology, New Delhi, India
for providing a DST-PURSE fellowship. K.S.V. and A.C.C. thank DST-SERB,
India (sanction No. SB/FT/CS-147/2013) for financial support. Authors
thank Prof. A. K. Srivastava, Director National Centre for Nanosciences
and Nanotechnology, University of Mumbai for his generous support.
Authors gratefully acknowledge V.N.K., A.A.C. and ORL, Department of
Chemistry, University of Mumbai for their generous help and support.
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O: 327.1497; found:
327.1500.
2-Phenyl-4-(p-tolyl)-1H-imidazole (5a)38
Supporting Information
Purified by column chromatography (EtOAc/PE 3:7) as a white solid;
yield: 105 mg (74%); mp 156–158 °C.
Supporting information for this article is available online at
1H NMR (400 MHz, CDCl3): δ = 9.17 (br s, 1 H), 7.83–7.81 (dd, J = 7.3,
3.6 Hz, 2 H), 7.52–7.50 (d, J = 8.0 Hz, 2 H), 7.18–7.12 (m, 3 H), 7.09 (s,
1 H), 7.03 (d, J = 7.9 Hz, 1 H), 2.22 (s, 3 H).
https://doi.org/10.1055/s-0036-1588585.
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References
13C NMR (100 MHz, CDCl3): δ = 146.3, 137.6, 129.5, 128.8, 128.3,
128.1, 127.9, 126.1, 125.3, 116.9, 21.3.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2: 235.1230; found:
235.1231.
(1) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Zhu, J. P.;
Bienaym, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
2005. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115. (d) Nicolaou, K.
C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551.
(e) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341. (f) Shindoh,
N.; Takemoto, Y.; Takasu, K. Chem. Eur. J. 2009, 15, 12168.
(2) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2014. (b) Pellissier, H.
Chem. Rev. 2013, 113, 442. (c) Tietze, L. F.; Kinzel, T.; Brazel, C. C.
Acc. Chem. Res. 2009, 42, 367. (d) Tietze, L. F.; Rackelmann, N.
Pure Appl. Chem. 2004, 76, 1967.
4-(4-Methoxyphenyl)-2-phenyl-1H-imidazole (5b)39
Purified by column chromatography (EtOAc/PE 3:7) as a white solid;
yield: 108 mg (76%); mp 260–262 °C.
1H NMR (400 MHz, CDCl3): δ = 8.58 (br s, 1 H), 7.80–7.73 (m, 2 H),
7.50 (d, J = 8.7 Hz, 1 H), 7.29–7.09 (m, 5 H), 6.97 (s, 1 H), 6.72 (d, J = 8.7
Hz, 1 H), 3.65 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.1, 146.4, 137.6, 130.5, 129.1,
(3) (a) Jin, Z. Nat. Prod. Rep. 2009, 26, 382. (b) Forte, B.; Malgesini,
B.; Piutti, C.; Quartieri, F.; Scolaro, A.; Papeo, G. Mar. Drugs
2009, 7, 705. (c) Midoux, P.; Pichon, C.; Yaouanc, J.-J.; Jaffrès, P.-
A. Br. J. Pharmacol. 2009, 157, 166. (d) Xiong, F.; Chen, X.-X.;
Chen, F.-E. Tetrahedron: Asymmetry 2010, 21, 665.
128.7, 126.6, 125.9, 125.6, 114.1, 113.2, 55.3.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O: 251.1179; found:
251.1180.
2-Phenyl-4-[3-(trifluoromethyl)phenyl]-1H-imidazole (5c)39
(4) (a) Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.;
Kumar, S.; Green, D.; McNulty, D.; Blumenthal, M. J.; Heys, J. R.;
Landvatter, S. W.; Strickler, J. E.; McLaughlin, M. M.; Siemens, I.
R.; Fisher, S. M.; Livi, G. P.; White, J. R.; Adams, J. L.; Young, P. R.
Nature (London) 1994, 372, 739. (b) de Laszlo, S. E.; Hacker, C.;
Li, B.; Kim, D.; MacCoss, M.; Mantlo, N.; Pivnichny, J. V.; Colwell,
L.; Koch, G. E.; Cascieri, M. A.; Hagmann, W. K. Bioorg. Med.
Chem. Lett. 1999, 9, 641. (c) Antolini, M.; Bozzoli, A.; Ghiron, C.;
Kennedy, G.; Rossi, T.; Ursini, A. Bioorg. Med. Chem. Lett. 1999, 9,
1023. (d) 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. (e) Dietrich, J.;
Purified by column chromatography (EtOAc/PE 3:7) as a yellow solid;
yield: 101 mg (68%); mp 264–266 °C.
1H NMR (400 MHz, CDCl3): δ = 9.94 (br s, 1 H), 7.94 (s, 1 H), 7.83 (dis-
torted t, J = 8.8, 7.3 Hz, 3 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.39 (t, J = 7.7 Hz,
1 H), 7.28–7.25 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 147.9, 138.5, 133.4, 131.4–130.5 [q, J =
32.2 Hz, 1 C (-CF3)], 129.2, 129.1, 128.8, 128.3, 125.8, 125.5, 123.6,
122.8, 120.1, 117.0.
HRMS (ESI): m/z [M + H]+ calcd for C16H12F3N2: 289.0947; found:
289.0948.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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S. D. Pardeshi et al.
Paper
Synthesis
Gokhale, V.; Wang, X.; Hurley, L. H.; Flynn, G. A. Bioorg. Med.
Chem. 2010, 18, 292. (f) Cho, H. J.; Gee, H. Y.; Baek, K.-H.; Ko, S.-
K.; Park, J.-M.; Lee, H.; Kim, N.-D.; Lee, M. G.; Shin, I. J. Am.
Chem. Soc. 2011, 133, 20267.
Chem. Commun. 1978, 562. (c) Porta, F.; Crotti, C.; Cennini, S.
J. Mol. Catal. 1989, 50, 333. (d) Bailey, A. J.; James, B. R. Chem.
Commun. 1996, 2343.
(15) Kison, C.; Opatz, T. Chem. Eur. J. 2009, 15, 843.
(16) Hu, B.; Wang, Z.; Ai, N.; Zheng, J.; Liu, X.-H.; Shan, S.; Wang, Z.
Org. Lett. 2011, 13, 6362.
(17) (a) Tang, D.; Wu, P.; Liu, X.; Chen, Y.-X.; Guo, S.-B.; Chen, W.-L.;
Li, J.-G.; Chen, B.-H. J. Org. Chem. 2013, 78, 2746. (b) Liu, X.;
Wang, D.; Chen, B. Tetrahedron 2013, 69, 9417. (c) Mitra, S.;
Bagdi, A. K.; Majee, A.; Hajra, A. Tetrahedron Lett. 2013, 54, 4982.
(d) Kumar, T.; Verma, D.; Menna-Barreto, R. F. S.; Valença, W. O.;
da Silva Júnior, E. N.; Namboothiri, I. N. N. Org. Biomol. Chem.
2015, 13, 1996.
(18) (a) Nie, Y.-B.; Wang, L.; Ding, M.-W. J. Org. Chem. 2012, 77, 696.
(b) Jiang, Z.; Lu, P.; Wang, Y. Org. Lett. 2012, 14, 6266. (c) Liu, X.;
Wang, D.; Chen, Y.; Tang, D.; Chen, B. Adv. Synth. Catal. 2013,
355, 2798. (d) Chen, C.-Y.; Hu, W.-P.; Yan, P.-C.; Senadi, G. C.;
Wang, J.-J. Org. Lett. 2013, 15, 6116. (e) Pusch, S.; Opatz, T. Org.
Lett. 2014, 16, 5430. (f) Aly, S.; Romashko, M.; Arndtsen, B. A.
J. Org. Chem. 2015, 80, 2709.
(19) Tlahuext-Aca, A.; Hernández-Fajardo, O.; Arévalo, A.; García, J. J.
Dalton Trans. 2014, 43, 15997.
(20) Cardoso, A. L.; Lemos, A.; Pinho e Melo, T. M. V. D. Eur. J. Org.
Chem. 2014, 5159.
(21) Chen, H.; Chiba, S. Org. Biomol. Chem. 2014, 12, 42.
(22) Adib, M.; Ansari, S.; Feizi, S.; Damavandi, J. A.; Mirzaei, P. Synlett
2009, 3263.
(23) Auricchio, S.; Truscello, A. M.; Lauria, M.; Meille, S. V. Tetrahedron
2012, 68, 7441.
(24) Qu, J.; Wu, P.; Tang, D.; Meng, X.; Chen, Y.; Guo, S.; Chen, B. New
J. Chem. 2015, 39, 4235.
(25) Hota, P. K.; Vijaykumar, G.; Pariyar, A.; Sau, S. C.; Sen, T. K.;
Mandal, S. K. Adv. Synth. Catal. 2015, 357, 3162.
(26) Li, J.; Neuville, L. Org. Lett. 2013, 15, 1752.
(27) Sharma, A. K.; Mazumdar, S. N.; Mahajan, M. P. J. Chem. Soc.,
Perkin Trans. 1 1997, 3065.
(28) (a) Zhou, X.; Ma, H.; Shi, C.; Zhang, Y.; Liu, X.; Huang, G. Eur. J.
Org. Chem. 2017, 237. (b) Zhu, Y.; Li, C.; Zhang, J.; She, M.; Sun,
W.; Wan, K.; Wang, Y.; Yin, B.; Liu, P.; Li, J. Org. Lett. 2015, 17,
3872.
(29) (a) Kalmode, H. P.; Vadagaonkar, K. S.; Murugan, K.; Chaskar, A.
C. New J. Chem. 2015, 39, 4631. (b) Kalmode, H. P.; Vadagaonkar,
K. S.; Murugan, K.; Prakash, S.; Chaskar, A. C. RSC Adv. 2015, 5,
35166. (c) Vadagaonkar, K. S.; Kalmode, H. P.; Prakash, S.;
Chaskar, A. C. New J. Chem. 2015, 39, 3639. (d) Vadagaonkar, K.
S.; Kalmode, H. P.; Murugan, K.; Chaskar, A. C. RSC Adv. 2015, 5,
5580. (e) Vadagaonkar, K. S.; Murugan, K.; Chaskar, A. C.; Bhate,
P. M. RSC Adv. 2014, 4, 34056.
(5) (a) Bonezzi, K.; Taraboletti, G.; Borsotti, P.; Bellina, F.; Rossi, R.;
Giavazzi, R. J. Med. Chem. 2009, 52, 7906. (b) Sadek, B. Pharma
Chem. 2011, 3, 410. (c) Jin, C. H.; Krishnaiah, M.; Sreenu, D.;
Subrahmanyam, V. B.; Rao, K. S.; Lee, H. J.; Park, S. J.; Park, H. J.;
Lee, K.; Sheen, Y. Y.; Kim, D. K. J. Med. Chem. 2014, 57, 4213.
(d) Zhang, L.; Peng, X.-M.; Damu, G. L. V.; Geng, R.-X.; Zhou, C.-
H. Med. Res. Rev. 2014, 34, 340.
(6) (a) Wolff, D. J.; Datto, G. A.; Samatovicz, R. A. J. Biol. Chem. 1993,
268, 9430. (b) Sennequier, N.; Wolan, D.; Stuehr, D. J. J. Biol.
Chem. 1999, 274, 930. (c) Koga, H.; Nanjoh, Y.; Makimura, K.;
Tsuboi, R. Med. Mycol. 2009, 47, 640. (d) Röhrig, U. F.; Majjigapu,
S. R.; Chambon, M.; Bron, S.; Pilotte, L.; Colau, D.; Van den
Eynde, B. J.; Turcatti, G.; Vogel, P.; Zoete, V.; Michielin, O. Eur. J.
Med. Chem. 2014, 84, 284.
(7) (a) Fukui, M.; Inaba, M.; Tsukagoshi, S.; Sakural, Y. Cancer Res.
1982, 42, 1098. (b) Atwell, G. J.; Fan, J.-Y.; Tan, K.; Denny, W. A.
J. Med. Chem. 1998, 41, 4744. (c) Al-Raqa, S. Y.; ElSharief, A. M.
S.; Khalil, S. M. E.; Al-Amri, A. M. Heteroat. Chem. 2006, 17, 634.
(8) (a) Vijesh, A. M.; Isloor, A. M.; Telkar, S.; Peethambar, S. K.; Rai,
S.; Isloor, N. Eur. J. Med. Chem. 2011, 46, 3531. (b) Choi, J. Y.;
Plummer, M. S.; Starr, J.; Desbonnet, C. R.; Soutter, H.; Chang, J.;
Miller, J. R.; Dillman, K.; Miller, A. A.; Roush, W. R. J. Med. Chem.
2012, 55, 852. (c) Yurttaş, L.; Duran, M.; Demirayak, Ş.; Gençer,
H. K.; Tunalı, Y. Bioorg. Med. Chem. Lett. 2013, 23, 6764.
(9) Vlahakis, J. Z.; Lazar, C.; Crandall, I. E.; Szarek, W. A. Bioorg. Med.
Chem. 2010, 18, 6184.
(10) (a) Adams, J. L.; Boehm, J. C.; Gallagher, T. F.; Kassis, S.; Webb, E.
F.; Hall, R.; Sorenson, M.; Garigipati, R.; Griswold, D. E.; Lee, J. C.
Bioorg. Med. Chem. Lett. 2001, 11, 2867. (b) Husain, A.; Drabu, S.;
Kumar, N.; Alam, M. M.; Bawa, S. J. Pharm. BioAllied Sci. 2013, 5,
154.
(11) (a) Maeda, Y.; Nishimura, T.; Uemura, S. Bull. Chem. Soc. Jpn.
2003, 76, 2399. (b) Asensio, J. A.; Gómez-Romero, P. Fuel Cells
2005, 5, 336. (c) Singh, N.; Jang, D. O. Org. Lett. 2007, 9, 1991.
(d) Nagarajan, N.; Velmurugan, G.; Prakash, A.; Shakti, N.;
Katiyar, M.; Venuvanalingam, P.; Renganathan, R. Chem. Asian J.
2014, 9, 294. (e) Kwon, J. E.; Park, S.; Park, S. Y. J. Am. Chem. Soc.
2013, 135, 11239. (f) Yuan, Y.; Chen, J.-X.; Lu, F.; Tong, Q.-X.;
Yang, Q.-D.; Mo, H.-W.; Ng, T.-W.; Wong, F.-L.; Guo, Z.-Q.; Ye, J.;
Chen, Z.; Zhang, X.-H.; Lee, C.-S. Chem. Mater. 2013, 25, 4957.
(g) Jeżewski, A.; Hammann, T.; Cywiński, P. J.; Gryko, D. T.
J. Phys. Chem. B 2015, 119, 2507.
(12) (a) Mowry, D. T. Chem. Rev. 1948, 42, 189. (b) Ellis, G. P.;
Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779. (c) Bacon, R.
G. R.; Hill, H. A. O. J. Chem. Soc. 1964, 1097. (d) Sandmeyer, T.
Ber. Dtsch. Chem. Ges. 1884, 17, 2650. (e) Koelsch, C. F.; Whitney,
A. G. J. Org. Chem. 1941, 6, 795.
(13) (a) Mori, K.; Yamaguchi, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
Chem. Commun. 2001, 461. (b) Yamaguchi, K.; Mizuno, N.
Angew. Chem. Int. Ed. 2003, 42, 1480. (c) Kotani, M.; Koike, T.;
Yamaguchi, K.; Mizuno, N. Green Chem. 2006, 8, 735. (d) Li, F.;
Chen, J.; Zhang, Q.; Wang, Y. Green Chem. 2008, 10, 553.
(e) Zhang, Y.; Xu, K.; Chen, X.; Hu, T.; Yu, Y.; Zhang, J.; Huang, J.
Catal. Commun. 2010, 11, 951.
(14) (a) Capdevielle, P.; Lavigne, A.; Sparfel, D.; Baranne-Lafont, J.;
Nguyen, K. C.; Maumy, M. Tetrahedron Lett. 1990, 31, 3305.
(b) Tang, R.; Diamond, S. E.; Neary, N.; Mares, F. J. Chem. Soc.,
(30) Chen, X.; Chen, T.; Ji, F.; Zhou, Y.; Yin, S.-F. Catal. Sci. Technol.
2015, 5, 2197.
(31) Yang, D.; Yan, K.; Wei, W.; Tian, L.; Shuai, Y.; Li, R.; You, J.; Wang,
H. Asian J. Org. Chem. 2014, 3, 969.
(32) Gandeepan, P.; Rajamalli, P.; Cheng, C.-H. Asian J. Org. Chem.
2014, 3, 303.
(33) Mahmudov, K. T.; Kopylovich, M. N.; Haukka, M.; Mahmudova,
G. S.; Esmaeila, E. F.; Chyragov, F. M.; Pombeiro, A. J. L. J. Mol.
Struct. 2013, 1048, 108.
(34) Jalal, S.; Sarkar, S.; Bera, K.; Maiti, S.; Jana, U. Eur. J. Org. Chem.
2013, 4823.
(35) Maiti, S.; Biswas, S.; Jana, U. J. Org. Chem. 2010, 75, 1674.
(36) Cooper, F. C.; Partridge, M. W. Org. Synth. 1956, 36, 64.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

J
S. D. Pardeshi et al.
Paper
Synthesis
(37) Tang, D.; Guo, X.; Wang, Y.; Wang, J.; Li, J.; Huang, Q.; Chen, B.
Tetrahedron Lett. 2015, 56, 5982.
(39) Zuliani, V.; Cocconcelli, G.; Fantini, M.; Ghiron, C.; Rivara, M.
J. Org. Chem. 2007, 72, 4551.
(38) Gopi, E.; Kumar, T.; Menna-Barreto, R. F. S.; Valença, W. O.;
da Silva Júnior, E. N.; Namboothiri, I. N. N. Org. Biomol. Chem.
2015, 13, 9862.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J