Selective synthesis of 1,4,5-trisubstituted imidazoles from α-imino ketones prepared by N-heterocyclic-carbene-catalyzed aroylation

Article abstract of DOI:10.1016/j.tet.2018.03.048

An alternative synthetic route to 1,4,5-trisubstituted imidazoles from α-imino ketone, which can be prepared from imidoyl chlorides and aromatic aldehydes via N-heterocycle carbene-catalyzed aroylation was developed. This methodology consists of simple tr

Full text of DOI:10.1016/j.tet.2018.03.048

Accepted Manuscript
Selective synthesis of 1,4,5-trisubstituted imidazoles from α-imino ketones prepared
by N-heterocyclic-carbene-catalyzed aroylation
Ryo Takashima, Kaoru Tsunekawa, Maki Shinozaki, Yumiko Suzuki
PII:
S0040-4020(18)30321-1
10.1016/j.tet.2018.03.048
TET 29388
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 February 2018
Revised Date: 20 March 2018
Accepted Date: 21 March 2018
Please cite this article as: Takashima R, Tsunekawa K, Shinozaki M, Suzuki Y, Selective synthesis
of 1,4,5-trisubstituted imidazoles from α-imino ketones prepared by N-heterocyclic-carbene-catalyzed
aroylation, Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.048.
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Selective Synthesis of 1,4,5-Trisubstituted
Imidazoles from α-Imino Ketones Prepared by
N-Heterocyclic Carbene-Catalyzed Aroylation
Leave this area blank for abstract info.
Ryo Takashimaa, Kaoru Tsunekawaa, Maki Shinozakia, and Yumiko Suzukia,
Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho,
Chiyoda-ku, Tokyo 102-8554, Japan

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Tetrahedron
journal homepage: www.elsevier.com
Selective Synthesis of 1,4,5-Trisubstituted Imidazoles from α-Imino Ketones
Prepared by N-Heterocyclic-Carbene-Catalyzed Aroylation
Ryo Takashimaa, Kaoru Tsunekawaa, Maki Shinozakia, and Yumiko Suzukia,
a Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An alternative synthetic route to 1,4,5-trisubstituted imidazoles from α-imino ketone, which can
be prepared from imidoyl chlorides and aromatic aldehydes via N-heterocyclec carbene-
catalyzed aroylation was developed. This methodology consists of simple transformations,
allowing a rapid access to imidazole derivatives with various aryl substituents at the desired
positions.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
N-heterocyclic carbene
Imidazole
Aroylation
Chemoselective reduction
Annulation
———
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
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1. Introduction
route to imidazoles. In our synthesis, the 1-, 4-, and 5-
substituents of imidazoles originate from the N-, 1-, and 2-
substituents of iminoethanones, respectively, allowing us to
access single isomers exclusively in contrast to the conventional
synthetic method for 1,4,5-substituted imidazoles (Scheme 1). In
other words, with an appropriate choice of starting materials, it is
possible to synthesize 1,4,5-trisubstituted triazoles bearing the
desired substituents at the expected positions.
N-Heterocyclic compounds are of great interest for drug
discovery and are widely used as active components of
pharmaceuticals. The high electronegativity of the nitrogen atom
results in polarization of the C–N bond, which allows interactions
between the heterocycle and biomolecules such as enzymes and
receptors, through hydrogen bond formation with hydrophilic
groups. Aromatic heterocycles can also interact through van der
Waals interactions.1
Among nitrogen-containing heterocycles, imidazoles are of
particular interest because of their abundance in biomolecules,
including histidine, histamine,2a cyano cobalamin,2b and bioactive
natural products such as sceptrin2c and nagelamides S2d.
Furthermore, they typically appear in biologically active
compounds such as anticancer,3 antibacterial,4 and antitubercular
agents.5 For example, dacarbazine is a chemotherapeutic agent
for the treatment of various cancers; the methyldiazonium ions
derived from its metabolism cause DNA methylation and
inhibition of cell proliferation.6 Another example is SK&F
Scheme 1. Synthesis of heterocycles from α-imino ketones
86002,
a pyridinyl imidazole-based p38 mitogen-activated
2. Results and discussion
protein kinase inhibitor with anti-inflammatory activity owing to
the downregulation of inflammatory cytokine production in the
monocyte/macrophage cell line THP-1.7 Moreover, SK&F 86002
and its analogues have been used to treat Ebola virus infections.8
First, the NHC-catalyzed aroylation was examined based on
our previously reported procedure (Scheme 2).20 Starting N-
arylbenzimidoyl chlorides 1 were easily prepared by chlorination
of the corresponding N-arylbenzamides. The reaction of 1 with
aromatic aldehydes (1.5 equiv) in THF for 6–9 h in the presence
of the NHC derived from the 1,3-dimethylimidazolium iodide
precursor (3 mol%) and sodium hydride (1.1 equiv) afforded the
desired α-imino ketones (for reaction mechanism, see the
Supplementary data). As shown in the mechanism in Scheme 3,
the NHC-catalyzed aroylation of 1 proceeded through the
Breslow intermediate, which was formed from the aldehyde and
the carbene generated by abstraction of the proton at the 2-
position of the imidazolium salt and served as an acyl anion
equivalent. The substrate scope of the reaction was investigated,
and the results are summarized in Scheme 2. Electron-deficient
benzimidoyl chlorides and sterically hindered naphthyl
derivatives were well tolerated to give the corresponding adducts
in moderate to high yields (2b–2e, 2j). The reaction of N-(4-
methoxyphenyl)benzimidoyl chloride provided aroylated
compound 2h in low yield, presumably because of the low
electrophilicity of the imino carbon atom owing to the electron-
donating effect of the N-4-methoxyphenyl group. This effect was
confirmed by the aroylation of benzimidoyl chlorides bearing an
aliphatic substituent on the imine nitrogen atom, which did not
afford the corresponding α-imino ketones. However, this finding
is contrary to the report by Huang et al., which indicates that N-
(n-octyl)trifluoroacetimidoyl chloride gives the corresponding
aroylated compound under similar conditions.21
Imidazoles and their salts also have many other applications,
e.g., in materials science9 and synthetic organic chemistry.10, 11 In
particular, 2-substituted imidazole derivatives, such as 2-
ethylimidazole, are widely used as hardeners for epoxy resins in
the materials industry.12 Moreover, N-heterocyclic carbenes
(NHCs) generated from imidazolium salts can act as ligands for
transition metal catalysts and as organocatalysts for reactions
such as umpolung and homoenolate reactions.11 In addition, N,N-
dialkylimidazolium salts are among the most widely used ionic
liquids, which find application as electrolytes and reaction
solvents.13 Because of their numerous advantages, the
development of new and efficient synthetic methods to access
imidazole derivatives is a subject of interest in various fields.
The classical methods for the construction of imidazole rings
include condensation of benzils with two equivalents of
formamide,14 and amination of α-bromo ketones followed by
annulation of the resulting amino ketones with formamide.15 In
addition, to date, various synthetic strategies have been
developed to prepare imidazoles, such as pivalic acid –promoted
multicomponent reaction involving the oxidation of internal
alkynes to form benzil intermediates followed by
cyclocondensation of amidines,16 and metal-catalyzed domino
reaction of propargylamines with tert-butylisonitrile.17 In
particular, a number of transition metal-catalyzed approaches
have been reported.18 However, to the best of our knowledge, the
selective synthesis of arbituarily substituted triarylimidazoles
from commercially available and inexpensive starting materials
remains a challenge. Recently, Ila et al. reported a one-pot
synthesis of 2,4,5-trisubstituted imidazoles from 1,3-bisaryl-
monothio-1,3-diketones.19 However, efficient and general
methods for the regioselective synthesis of multisubstituted
imidazoles have not yet been developed.
The subsequent selective reduction of a functional group can
be challenging in the presence of other functional groups with
similar chemical reactivity, such as carbonyl and imino groups.
Our preliminary studies showed that the reducing agents
commonly used in reductive amination reactions, namely,
sodium triacetoxyborohydride, sodium cyanoborohydride, and
Hantzsch ester, were not suitable for the chemoselective
reduction of α-imino ketones (see Supplementary data). To
overcome this problem, we used 2-picoline borane, which was
previously reported as an alternative reagent for reductive
amination.22 An evaluation of reduction conditions revealed that
high yields were achieved by using an equimolar amount of 2-
picoline borane at room temperature in the presence of a catalytic
amount of phenylphosphinic acid (Table 1).
With this motivation, we investigated a straightforward
selective route to trisubstituted imidazoles, which includes an
NHC-catalyzed aroylation reaction, chemoselective reduction of
the imino group, and annulation between the resulting secondary
amine and formamide. Our recently reported protocol for the
synthesis of pyradines and quinoxalines from α-imino ketones as
versatile intermediates also urged us to develop a new synthetic

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Scheme 4. Substrate scope of the chemoselective reduction.
Scheme 2. Substrate scope of the aroylation reaction.
a
b
a Previous data reported by our group. 1.3 equiv of NaH was used.20
20 mol% of phenylphosphinic acid was used.
50 mol% of
phenylphosphinic acid was used, and the reaction was conducted in
MeOH/CH2Cl2 (5/1).
Next, the annulation between α-amino ketones and formamide
to form the corresponding imidazoles was examined (Table 2).
The reaction conditions were optimized using compound 3a as a
model substrate. First, formamide solutions containing high (M =
0.4) or low (M = 0.03) concentrations of 3a were heated in an
open system (Table 2, entries 1, 2). However, the desired
compound was not obtained owing to rapid self-condensation of
3a. Thus, to prevent self-condensation, an ethyl acetate solution
of 3a was added over 1 h to a large excess of formamide at 180
°C, and the reaction was continued at the same temperature for 7
h to afford desired imidazole 4a in low yield (Table 2, entries 3,
4).
Scheme 3. Mechanism of the aroylation reaction
Table 1. Optimization of the chemoselective reduction
conditions
When THF was used instead of ethyl acetate, the yield of 4a
increased up to 72% (Table 2, entry 6). Other attempts were
made to further improve the efficiency of the annulation. A
slower addition rate of the THF solution of 3a by using a syringe
pump under an argon atmosphere combined with the use of
diethyl ether as the extraction solvent instead of ethyl acetate led
to an improved yield (Table 2, entry 7). With the aim of
accelerating the reaction, a Brønsted acid was tested as a catalyst,
but a lower yield was observed (Table 2, entries 8, 9). Moreover,
addition of a Lewis acid or a hypervalent iodine reagent22 was not
beneficial for the annulation, instead promoting the three-
component condensation of formamide (Table 2, entries 10, 11).
These results indicate that the transformation should be carried
out under an argon atmosphere, and that an acidic environment
was detrimental to the reaction rate and yield. Moreover, the slow
addition of the α-amino ketone in THF via a syringe pump over 2
h was found to be crucial.
Entry
1
Pic-BH3 (mol%)
33
Condition
Yield (%)
22
6 h, 0 °C, AcOH (excess)
2
3
4
5
6
7
33
50
6 h, 0 °C, C6H5P(O)(OH)Ha
8 h, rt, C6H5P(O)(OH)Ha
6 h, rt, C6H5P(O)(OH)Ha
6 h, rt, C6H5P(O)(OH)Ha
6 h, rt, C6H5P(O)(OH)Hb
6 h, rt, AcOH (excess)
21
53
66
74
100
100
100
84
84
78
a
b
100 mol% of phenylphosphinic acid was used.
phenylphosphinic acid was used.
20 mol% of
With the optimized conditions in hand, the substrate scope of
the chemoselective reduction was investigated (Scheme 4). Imine
moieties bearing an electron-withdrawing or electron-donating
group were selectively reduced to afford the desired secondary
amines (3b, 3c, 3e, 3h, 3i, 3j). Substrates with a naphthyl or
heteroaryl substituent were also applicable to the reaction to give
3d, 3j or 3f, respectively. On the other hand, the reaction of 2g
was sluggish, probably because of the low reactivity of the imino
carbon owing to the push-pull structure.
We next investigated the scope of the annulation reaction
using a variety of α-amino ketones (Scheme 5). Under the
optimized conditions, both electron-rich and electron-deficient
aromatic substrates afforded the corresponding imidazoles in
good yields. Notably, the reaction of nitro substituted α-amino
ketones 3e and 3g did not proceed at all, probably because of
their instability and the low nucleophilicity of the amino group,
and the corresponding oxidation products, i.e., α-imino ketones
2e and 2g, were obtained.

4
Tetrahedron
performed under argon and stirring unless otherwise noted.
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Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on JEOL JNM-ECX (300 and 500 MHz)
Table 2. Optimization of the annulation conditions
a
spectrometer. Chemical shifts were recorded in parts per million
1
(ppm, δ) relative to tetramethylsilane (δ 0.00). H NMR splitting
patterns are designated as singlet (s), doublet (d), triplet (t), dd
(doublet of doublets), dt (doublet of triplets), m (multiplets), etc.
Carbon nuclear magnetic resonance (13C NMR) spectra were
recorded on a JEOL JNM-ECX (75 and 125 MHz) spectrometer.
Mass spectra were recorded using a TOF (ESI) analyzer or a
magnetic sector (FAB) analyzer, and IR spectra were recorded on
a JASCO FT-IR 4100 spectrometer. Melting points were
measured using an ATM-02, AS ONE melting point apparatus.
Medium-pressure liquid chromatography was performed using a
Yamazen YFLC W-Prep 2XY system. For slow addition of
solutions, a SIMDOS® 02 diaphragm dosing pump (KNF Japan)
was used. Column chromatography was performed using acidic
Wako-gel 300 (45–75 µm) by Wako Chemicals. For thin-layer
chromatography (TLC) analysis, Merck TLC plates (silica gel
60G F254 0.25 mm) were used. The TLC plates were visualized
by fluorescence under a UV lamp (254 or 365 nm).
Entry
1
NH2CHO (mL)
5 (M = 0.4)
Co-solvent
-
Condition
140 °C
Yield (%)
n.d.
n.d.
10
2
3a
4a
5a
6a
7b
8b
9b
35 (M = 0.03)
30 (M = 0.04)
50 (M = 0.02)
30 (M = 0.05)
50 (M = 0.03)
50 (M = 0.02)
50 (M = 0.02)
50 (M = 0.02)
50 (M = 0.03)
50 (M = 0.02)
-
200 °C
AcOEt
AcOEt
THF
180 °C
180 °C
55
180 °C
51
THF
180 °C
72
THF
180 °C
83
THF
180 °C, AcOH
180 °C, HCl
120 °C, BF3・Et2O
rt, PIFAc
77
THF
59
10b
11b
THF
21
THF
trace
a
Addition over 1 h using a dropping funnel, and a reaction time of 7 h. b
Addition over 2 h using a syringe pump under an argon atmosphere, and a
reaction time of 8 h. c PIFA: [bis(trifluoroacetoxy)iodo]benzene.23
3.1.1. General procedure for synthesis of α-imino ketones
To N-arylimidoyl chlorides (10.4 mmol) in two-necked flask
equipped with a magnetic stir bar, 1.5 equiv. of aromatic
aldehyde (16.1 mmol), 3 mol % of 1.3-dimethyimidazolium
iodide (0.0701 g, 0.313 mmol) and THF (60 mL) was addded,
then 1.1 equiv. of sodium hydride (0.458g, 11.4 mmol) was
added at 0 °C, and the resulting solution was stirred at reflux
temperature for 6 - 9 hours. After completion of the reaction, the
solution was poured into ice water (50 mL), extracted three times
with AcOEt. The organic layer was washed with brine, and dried
over Na2SO4. After filtration and concentration under reduced
pressure, the residue was purified by silica gel column
chromatography (n-hexane: AcOEt = 24: 1) to afford α-imino
ketones 2a – 2j.
3.1.1.1. 1,2-Diphenyl-2-(phenylimino)ethanone (2a24). Yellow
solid (recrystallized from AcOEt/n-hexane); 70% yield (1.50 g),
1
Rf = 0.51 (9:1 n-hexane/AcOEt), H NMR (300 MHz, CDCl3): δ
= 7.89 (dt, J = 6.4, 1.7 Hz, 2H), 7.76 (dt, J = 7.7, 1.2 Hz, 2H),
7.51-7.42 (m, 4H), 7.34 (t, J = 7.6 Hz, 2H), 7.13 (t, J = 7.7 Hz,
2H), 6.95-6.87 (m, 3H), 13C NMR (125 MHz, CDCl3): δ = 197.6,
177.5, 166.2, 149.2, 135.1, 134.6, 134.3, 131.6, 128.8, 128.6,
128.1, 124.6, 120.4.
Scheme 5. Substrate scope of the annulation reaction.
In summary, we have developed a regioselective synthesis of
1,4,5-triaryl imidazoles from easily accessible starting materials.
The key reactions are NHC-catalyzed aroylation of imidoyl
chlorides with aromatic aldehydes, chemoselective reduction of
the aroylated compounds, and annulation of the resulting α-
amino ketones with formamide. This methodology allows rapid
access to imidazole derivatives, paving the way for the
construction of chemical libraries that will be of great value in
the pharmaceutical and agrochemical industries. Further
derivatization of the resulting imidazoles, such as regioselective
functionalization, is in progress and will be reported in due
course.
3.1.1.2. 2-(3-Chlorophenyl)-1-phenyl-2-(phenylimino)ethanone
(2c25). Yellow solid (recrystallized from AcOEt/n-hexane); 73%
1
yield (1.51 g); Rf = 0.49 (9:1 n-hexane/AcOEt); H NMR (300
MHz, CDCl3): δ = 7.98 (t, J = 1.6 Hz, 1H), 7.74 (dt, J = 8.4, 1.6
Hz, 2H), 7.68 (dt, J = 7.8, 1.6 Hz, 1H), 7.52-7.45 (m, 2H), 7.39-
7.32 (m, 3H), 7.14 (t, J = 8.4 Hz, 2H), 6.97-6.86 (m, 3H); 13C
NMR (75 MHz, CDCl3): δ = 196.9, 164.7, 148.7, 136.7, 135.01,
134.47, 134.2, 131.6, 130.0, 129.2, 128.8, 128.6, 127.7, 126.4,
125.0, 120.3.
3.1.1.3. 2-(Naphthalene-2-yl)-1-phenyl-2-(phenylimino)ethanone
(2d). Yellow solid (recrystallized from AcOEt/n-hexane); 45%
yield (0.949 g); mp 151 – 153 °C; Rf = 0.44 (9:1 n-
hexane/AcOEt); IR (FT): cm-1 = 1666 (C=O), 1H-NMR (300
MHz, CDCl3): δ = 8.25 (dd, J = 8.6, 1.7 Hz, 1H), 8.11 (s, 1H),
7.94 (d, J = 8.6 Hz, 1H), 7.88-7.78 (m, 4H), 7.58-7.45 (m, 3H),
7.34 (t, J = 7.8 Hz, 2H), 7.15 (t, J = 7.8 Hz, 2H), 6.94 (t, J = 8.4
Hz, 3H); 13C-NMR (125 MHz, CDCl3): δ = 197.6, 166.3, 134.9,
134.8, 134.3, 132.8, 132.5, 130.0, 129.3, 129.1, 128.8, 128.6,
127.9, 127.8, 126.7, 124.7, 123.7, 120.5; HRMS (FAB): m/z
3. Experimental
3.1. Materials & methods
Reagents and solvents were purchased from commercial
sources and used without further purification. All reactions were

[335.1310] calcd. for C24H18NO (M+H): 336.1388; found:
336.1389.
3.1.2.1. 1,2-Diphenyl-2-(phenylamino)ethanone (3a26). Yellow
solid (recrystallized from CH2Cl2/n-hexane); 84% yield (0.705
g); Rf = 0.35 (n-hexane: AcOEt = 8 : 1); H NMR (300 MHz,
CDCl3): δ = 8.00 (dt, J = 6.8, 1.5 Hz, 2H), 7.54 (tt, J = 7.3, 1.6
Hz, 1H), 7.46-7.40 (m, 4H), 7.31-7.10 (m, 5H), 6.70-6.65 (m,
3H), 6.02 (d, J = 6.4 Hz, 1H), 5.40 (d, J = 6.4 Hz, 1H); 13C NMR
(125 MHz, CDCl3): δ = 197.0, 146.1, 137.7, 135.1, 133.5, 129.2,
129.0, 128.9, 128.7, 128.4, 128.1, 117.8, 113.5, 62.7.
ACCEPTED MANUSCRIPT
1
3.1.1.4.
2-(4-Methoxyphenylimino)-2-(4-nitrophenyl)-1-
phenylethanone (2g). Orange solid (recrystallized from AcOEt/n-
hexane); 77% yield (1.31 g); mp 128 – 129 °C; Rf = 0.22 (9:1 n-
hexane/AcOEt); IR (FT): cm-1 = 1662 (C=O), 1521, 1504, 1362,
1
1343 (NO2); H NMR (300 MHz, CDCl3): δ = 8.27 (dt, J = 9.2,
2.2 Hz, 2H), 8.05 (dt, J = 9.2, 2.2 Hz, 2H), 7.75 (d, J = 7.4 Hz,
2H), 7.52 (tt, J = 7.4, 1.4 Hz, 1H), 7.37 (t, J = 7.4 Hz, 2H), 6.96
(dt, J = 9.6, 2.8 Hz, 2H), 6.71 (dt, J = 9.6, 2.8 Hz, 2H), 3.70 (s,
3H); 13C NMR (125 MHz, CDCl3): δ = 198.0, 162.3, 157.9,
149.2, 141.4, 140.8, 134.8, 133.9, 129.2, 129.1, 128.8, 123.9,
122.7, 114.1, 55.3; HRMS (FAB): m/z [360.1110] calcd. for
C21H17N2O4 (M+H): 361.1188; found: 361.1199.
3.1.2.2. 2-(4-Chlorophenyl)-1-phenyl-2-(phenylamino)ethanone
(3b). Yellow solid (recrystallized from CH2Cl2/n-hexane); 82%
yield (0.685 g); mp 112 – 114 °C; Rf = 0.34 (8:1 n-
1
hexane/AcOEt); IR (FT): cm-1 = 3417 (N-H), 1669 (C=O); H
NMR (500 MHz, CDCl3): δ = 7.97 (d, J = 7.4 Hz, 2H), 7.56 (t, J
= 7.4 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.38 (dt, J = 9.0, 2.3 Hz,
2H), 7.23-7.25 (m, 2H) , 7.13 (t, J = 7.6 Hz, 2H), 6.70 (t, J = 7.6
Hz, 1H), 6.64 (d, J = 7.6 Hz, 2H), 6.00 (d, J = 5.5 Hz, 1H), 5.42
(d, J = 5.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 196.6,
145.8, 136.3, 134.8, 134.0, 133.7, 129.4, 129.29, 129.25, 128.8,
128.8, 118.1, 113.5, 61.9; HRMS (FAB): m/z [321.0920] calcd.
for C20H17ClNO (M+H): 322.0999; found: 322.0993.
3.1.1.5.
1-(4-Chlorophenyl)-2-(4-methoxyphenylimino)-2-
phenylethanone (2h). Orange solid (recrystallized from
CH2Cl2/n-hexane); 22% yield (0.154 g); mp 146 – 147 °C; Rf =
1
0.39 (9:1 n-hexane/AcOEt); H NMR (500 MHz, CDCl3): δ =
7.84 (d, J = 6.9 Hz, 2H) , 7.70 (dt, J = 8.8, 2.1 Hz, 2H), 7.49-7.41
(m, 3H), 7.31 (d, J = 8.6 Hz, 2H), 6.88 (dt, J = 9.7, 2.7 Hz, 2H),
6.69 (dt, J = 9.7, 2.7 Hz, 2H), 3.70 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ = 197.5, 164.8, 157.1, 142.1, 141.0, 135.1, 132.8,
131.5, 130.5, 129.3, 128.8, 127.9, 122.2, 114.0, 55.3; HRMS
(FAB): m/z [349.0870] calcd. for C21H17ClNO2 (M+H):
350.0948; found: 350.0953.
3.1.2.3. 2-(3-Chlorophenyl)-1-phenyl-2-(phenylamino)ethanone
(3c). Yellow oil; 86% yield (0.634 g); Rf = 0.33 (8:1 n-
1
hexane/AcOEt); IR (FT): cm-1 = 3400 (N-H), 1683 (C=O); H
NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 7.4 Hz, 2H), 7.57 (t, J
= 7.4 Hz, 1H), 7.44-7.48 (m, 3H), 7.34 (d, J = 7.4 Hz, 1H), 7.13-
7.23 (m, 4H), 6.65-6.72 (m, 3H), 5.99 (d, J = 6.1 Hz, 1H), 5.43
(d, J = 6.1 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 196.4,
145.7, 139.9, 134.9, 134.7, 133.8, 130.2, 129.3, 128.82, 128.77,
128.3, 128.0, 126.3, 118.1, 113.4, 62.0; HRMS (FAB): m/z
[321.0920] calcd. for C20H17ClNO (M+H): 322.0999; found:
322.0991.
3.1.1.6.
2-(4-Chlorophenylimino)-1-(4-methoxyphenyl)-2-
phenylethanone (2i). Yellow solid (recrystallized from AcOEt/n-
hexane); 67% yield (1.48 g); mp 120 – 122 °C; Rf = 0.29 (9:1 n-
1
hexane/AcOEt); IR (FT): cm-1 = 1663 (C=O); H NMR (300
MHz, CDCl3): δ = 7.87 (dt, J = 7.3, 2.2 Hz, 2H) , 7.73 (dt, J =
9.4, 2.4 Hz, 2H), 7.50-7.41 (m, 3H), 7.11 (dt, J = 9.4, 2.4 Hz,
2H), 6.86-6.81 (m, 4H), 3.82 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ = 195.3, 190.8, 167.1, 164.6, 147.9, 135.0, 131.8,
129.9, 128.8, 128.7, 128.1, 127.6, 121.8, 114.3, 55.5; HRMS
(FAB): m/z [349.0870] calcd. for C21H17ClNO2 (M+H):
350.0948; found: 350.0959.
3.1.2.4. 2-(Naphthalene-2-yl)-1-phenyl-2-(phenylamino)ethanone
(3d). Yellow solid (recrystallized from CH2Cl2/n-hexane); 87%
yield (0.684 g); mp 133 – 135 °C; Rf = 0.34 (8:1 n-
1
hexane/AcOEt); IR (FT): cm-1 = 3407 (N-H), 1677 (C=O); H
NMR (300 MHz, CDCl3): δ = 8.03 (dt, J = 6.9, 1.6 Hz, 2H), 7.93
(d, J = 1.4 Hz, 1H), 7.80-7.73 (m, 3H), 7.56-7.39 (m, 6H), 7.12
(tt, J = 8.0, 1.9 Hz, 2H), 6.73-6.64 (m, 3H), 6.19 (d, J = 6.2 Hz,
1H), 5.51 (d, J = 6.2 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ =
197.0, 146.1, 135.2, 135.0, 133.5, 133.4, 133.0, 129.2, 129.0,
128.9, 128.7, 127.9, 127.6, 126.3, 125.4, 117.9, 113.5, 62.8;
HRMS (FAB): m/z [337.1467] calcd. for C24H20NO (M+H):
338.1545; found: 338.1551.
3.1.1.7.
2-(4-Chlorophenylimino)-2-(naphthalene-2-yl)-1-
phenylethanone (2j). Yellow solid (recrystallized from AcOEt/n-
hexane); 73% yield (1.36 g), mp 140 - 141 °C; Rf = 0.45 (9:1 n-
1
hexane/AcOEt); IR (FT): cm-1 = 1661 (C=O); H NMR (300
MHz, CDCl3): δ = 8.22 (dd, J = 8.6, 1.7 Hz, 1H), 8.09 (s, 1H),
7.94 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.83-7.78 (m,
3H), 7.58-7.46 (m, 3H), 7.36 (t, J = 7.7 Hz, 2H), 7.12 (dt, J = 9.2,
2.5 Hz, 2H), 6.87 (dt, J = 9.2, 2.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ = 197.2, 167.0, 147.8, 135.0, 134.6, 134.5, 132.7,
132.2, 130.2, 130.0, 129.3, 129.2, 129.0, 128.8, 128.1, 127.8,
126.8, 123.5, 121.9; HRMS (FAB): m/z [369.0920] calcd. for
C24H17ClNO (M+H): 370.0999; found: 370.1020.
3.1.2.5.
2-(4-Nitrophenyl)-1-phenyl-2-(phenylamino)ethanone
(3e). Yellow solid (recrystallized from CH2Cl2/n-hexane); 91%
yield (0.485 g); mp 58 – 60 °C; Rf = 0.18 (8:1 n-hexane/AcOEt);
IR (FT): cm-1 = 3378 (N-H), 1679 (C=O), 1521, 1342 (NO2); 1H-
NMR (500 MHz, CDCl3): δ = 8.13 (d, J = 8.6 Hz, 2H), 7.98 (d, J
= 8.0 Hz, 2H), 7.59-7.64 (m, 3H), 7.48 (t, J = 7.4 Hz, 2H), 7.15
(t, J = 8.0 Hz, 2H), 6.73 (t, J = 7.4 Hz, 1H), 6.64 (d, J = 7.4 Hz,
2H), 6.14 (d, J = 6.1 Hz, 1H), 5.53 (d, J = 6.1 Hz, 1H); 13C-NMR
(125 MHz, CDCl3): δ = 195.7, 147.6, 145.4, 145.3, 134.5, 134.2,
129.4, 129.0, 128.9, 124.2, 118.5, 113.5, 77.3, 62.1; HRMS
(FAB): m/z [332.1161] calcd. for C20H17N2O3 (M+H): 333.1239;
found: 333.1216.
3.1.2. General procedure for synthesis of α-amino ketones
For most of α-iminoketones (2d – 2j): A mixture of α-
iminoketones (3.02 mmol), 2-picolineborane (0.333 g, 3.02
mmol), and phenylphosphinic acid (0.0876 g, 0.61 mmol) in
MeOH and CH2Cl2 (24 mL, 5/1) was stirred at room temperature
for 6 - 9 hours. For other α-imino ketones (2a – 2c): The
reaction was carried out in MeOH. Then, 20 mL of water was
added and the mixture was evaporated to remove organic solvent.
Subsequently, the product was extracted three times with AcOEt
and the organic layer was washed with brine, and dried over
Na2SO4. After concentration under reduced pressure, the residue
was purified by silica gel column chromatography (n-hexane:
AcOEt = 9: 1) to afford α-aminoketones 3a – 3j.
3.1.2.6. 2-Phenyl-2-(phenylamino)-1-(thiophene-2-yl)ethanone
(3f). Light yellow solid (recrystallized from CH2Cl2/n-hexane);
89% yield (0.442 g); mp 138 – 140 °C; Rf = 0.32 (8:1 n-
1
hexane/AcOEt); IR (FT): cm-1 = 3397 (N-H), 1645 (C=O); H
NMR (500 MHz, CDCl3): δ = 7.89-7.88 (m, 1H), 7.65-7.64 (m,
1H), 7.51 (dt, J = 8.4, 1.7 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.26-
7.27 (m, 1H), 7.15-7.11 (m, 3H), 6.69-6.65 (m, 3H), 5.79 (s, 1H),
5.25 (s, 1H); 13C NMR (125 MHz, CDCl3): δ = 189.7, 146.0,

6
Tetrahedron
141.2, 137.9, 134.6, 133.2, 129.2, 129.0, 128.3, 128.2, 128.0,
chromatography (n-hexane: AcOEt = 2: 1) to afford imidazoles
ACCEPTED MANUSCRIPT
118.0, 113.5, 64.1; HRMS (FAB): m/z [293.0824] calcd. for
4a – 4j.
C18H16NOS (M+H): 294.0953; found: 294.0977.
3.1.3.1. 1,4,5-Triphenyl-1H-imidazole (4a27). 1,2-Diphenyl-2-
(phenylamino)ethanone 3a (0.542 g, 1.90 mmol) was reacted
with formamide according to general procedure 3.1.3. White
solid (recrystallized from CH2Cl2/n-hexane); 84% yield (0.280
g); Rf = 0.32 (2:1 n-hexane/AcOEt); 1H NMR (500 MHz, CDCl3):
δ = 7.78 (s, 1H), 7.54 (dd, J = 8.6, 1.1 Hz, 2H), 7.33-7.24 (m,
8H), 7.21-7.10 (m, 5H); 13C-NMR (125 MHz, CDCl3): δ = 138.9,
137.4, 136.4, 134.4, 130.8, 130.1, 129.2, 128.65, 128.56, 128.2,
128.1, 127.9, 127.2, 126.7, 125.8.
3.1.2.7.
2-(4-Methoxyphenylamino)-2-(4-nitrophenyl)-1-
phenylethanone (3g). Red solid (recrystallized from CH2Cl2/n-
hexane); 70% yield (0.241 g); mp 119 – 121 °C; Rf = 0.12 (8:1 n-
hexane/AcOEt); IR (FT): cm-1 = 3383 (N-H), 1685 (C=O); H
1
NMR (500 MHz, CDCl3): δ = 8.12 (dt, J = 9.0, 2.0 Hz, 2H), 7.96
(d, J = 7.8 Hz, 2H), 7.62-7.57 (m, 3H), 7.47 (t, J = 7.8 Hz, 2H),
6.73 (dt, J = 9.7, 2.9 Hz, 2H), 6.60 (dt, J = 9.7, 2.9 Hz, 2H), 6.07
(d, J = 5.4 Hz, 1H), 5.21 (d, J = 5.4 Hz, 1H), 3.70 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ = 196.2, 152.8, 147.6, 145.6, 139.4,
134.6, 134.1, 129.0, 128.9, 128.8, 124.2, 115.01, 114.98, 63.1,
55.7; HRMS (FAB): m/z [362.1267] calcd. for C21H18N2O4 (M):
362.1267; found: 362.1267.
3.1.3.2. 5-(4-Chlorophenyl)-1,4-diphenyl-1H-imidazole (4b). 2-
(4-Chlorophenyl)-1-phenyl-2-(phenylamino)ethanone 3b (0.228
g, 0.690 mmol) was reacted with formamide according to general
procedure. White solid (recrystallized from CH2Cl2/n-hexane);
65% yield (0.411 g); mp 171 – 172 °C; Rf = 0.29 (2:1 n-
hexane/AcOEt); 1H NMR (500 MHz, CDCl3): δ = 7.78 (d, J = 1.1
Hz, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.37-7.35 (m, 3H), 7.29-7.21
(m, 5H), 7.12-7.06 (m, 4H); 13C-NMR (125 MHz, CDCl3): δ =
139.4, 137.7, 136.2, 134.1, 132.0, 129.4, 128.9, 128.6, 128.3,
128.2, 127.3, 126.9, 125.8; HRMS (FAB): m/z [330.0924] calcd.
for C21H16ClN2 (M+H): 331.1002; found: 331.1009.
3.1.2.8.
1-(4-Chlorophenyl)-2-(4-methoxyphenylamino)-2-
phenylethanone (3h). Yellow solid (recrystallized from
CH2Cl2/n-hexane); 81% yield (0.143 g); mp 138 – 140 °C; Rf =
0.29 (8:1 n-hexane/AcOEt); IR (FT): cm-1 = 3399 (N-H), 1674
1
(C=O); H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 8.6 Hz,
2H), 7.41-7.21 (m, 7H), 6.72 (d, J = 9.4 Hz, 2H), 6.62 (dd, J =
9.4, 2.9 Hz, 2H), 5.90 (s, 1H), 5.03 (s, 1H), 3.71 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ = 196.3, 152.5, 140.2, 139.9, 137.6,
133.4, 130.2, 129.2, 129.0, 128.2, 128.1, 115.1, 114.9, 64.0, 55.7;
HRMS (FAB): m/z [351.1026] calcd. for C21H19ClNO2 (M+H):
352.1104; found: 352.1099.
3.1.3.3. 5-(3-Chlorophenyl)-1,4-diphenyl-1H-imidazole (4c). 2-
(3-Chlorophenyl)-1-phenyl-2-(phenylamino)ethanone 3c (0.334
g, 1.01 mmol) was reacted with formamide according to general
procedure. White solid (recrystallized from CH2Cl2/n-hexane);
75% yield (0.321 g); mp 139 – 141 °C; Rf = 0.33 (2:1 n-
3.1.2.9.
2-(4-Chlorophenylamino)-1-(4-methoxyphenyl)-2-
1
phenylethanone (3i). Yellow solid (recrystallized from CH2Cl2/n-
hexane); 90% yield (0.486 g); mp 131 – 133 °C; Rf = 0.23 (8:1 n-
hexane/AcOEt); H NMR (300 MHz, CDCl3): δ = 7.78 (s, 1H),
7.53 (dt, J = 6.3, 1.7 Hz, 2H), 7.37-7.35 (m, 3H), 7.31-7.10 (m,
8H), 7.03 (dt, J = 7.6, 1.4 Hz, 1H); 13C NMR (125 MHz, CDCl3):
δ = 139.6, 137.7, 136.1, 134.3, 134.0, 132.0, 130.6, 129.8, 129.4,
129.0, 128.3, 128.2, 127.3, 127.1, 127.0, 125.8; HRMS (FAB):
m/z [330.0924] calcd. for C21H16ClN2 (M+H): 331.1002, found:
331.0979.
hexane/AcOEt); IR (FT): cm-1 = 3398 (N-H), 1673 (C=O); H
1
NMR (500 MHz, CDCl3): δ = 8.03 (dt, J = 9.4, 2.3 Hz, 2H), 7.46
(d, J = 7.4 Hz, 2H), 7.32-7.27 (m, 2H), 7.23 (t, J = 7.4 Hz, 1H),
7.08 (dt, J = 9.6, 2.7 Hz, 2H), 6.92 (dt, J = 9.4, 2.3 Hz, 2H), 6.60
(dt, J = 9.6, 2.7 Hz, 2H), 5.96 (d, J = 6.9 Hz, 1H), 5.51 (d, J = 6.9
Hz, 1H), 3.84 (s, 3H), 13C NMR (125 MHz, CDCl3): δ = 194.9,
163.9, 144.7, 137.7, 131.2, 129.02, 128.97, 128.1, 127.9, 127.5,
122.2, 114.5, 113.9, 62.1, 55.4.; HRMS (FAB): m/z [351.1026]
calcd. for C21H19ClNO2 (M+H): 352.1104; found: 352.1070.
3.1.3.4. 5-(Naphthalen-2-yl)-1,4-diphenyl-1H-imidazole (4d). 2-
(Naphthalene-2-yl)-1-phenyl-2-(phenylamino)ethanone 3d (0.378
g, 1.09 mmol) was reacted with formamide according to general
procedure. White solid (recrystallized from CH2Cl2/n-hexane);
50% yield (0.184 g); mp 202 – 204 °C; Rf = 0.31 (2:1 n-
3.1.2.10.
2-(4-Chlorophenylamino)-2-(naphthalene-2-yl)-1-
phenylethanone (3j). Light yellow solid (recrystallized from
acetone/n-hexane); 89% yield (0.464 g); mp 156 – 158 °C; Rf =
0.37 (8:1 n-hexane/AcOEt); IR (FT): cm-1 = 3398 (N-H), 1673
1
hexane/AcOEt); H NMR (500 MHz, CDCl3): δ = 7.83-7.80 (m,
2H), 7.73 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 6.6 Hz, 2H), 7.56 (dd,
J = 6.6, 1.4 Hz, 2H), 7.50-7.44 (m, 2H), 7.31-7.13 (m, 9H); 13C
NMR (125 MHz, CDCl3): δ = 139.3, 137.6, 136.4, 134.4, 133.2,
132.7, 130.1, 129.3, 128.5, 128.21, 128.15, 128.1, 127.9, 127.7,
127.6, 127.3, 126.7, 126.5, 126.3, 125.8; HRMS (FAB): m/z
[346.1470] calcd. for C25H19N2 (M+H): 347.1548, found:
347.1538.
1
(C=O); H NMR (500 MHz, CDCl3): δ = 8.03 (d, J = 8.0 Hz,
2H), 7.90 (s, 1H), 7.74-7.79 (m, 3H), 7.41-7.54 (m, 6H), 7.05 (d,
J = 9.2 Hz, 2H), 6.63 (d, J = 9.2 Hz, 2H), 6.14 (d, J = 6.3 Hz,
1H), 5.55 (d, J = 6.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ =
196.5, 144.6, 134.8, 134.7, 133.7, 133.3, 133.0, 129.2, 129.1,
128.9, 128.7, 127.9, 127.70, 127.68, 126.4, 125.2, 114.6, 62.8;
HRMS (FAB): m/z [371.1077] calcd. for C24H19ClNO (M+H):
372.1155; found: 372.1174.
3.1.3.5. 1,5-Diphenyl-4-(thiophen-2-yl)-1H-imidazole (4f). 2-
Phenyl-2-(phenylamino)-1-(thiophene-2-yl)ethanone 3f (0.426 g,
1.41 mmol) was reacted with formamide according to general
procedure. White solid (recrystallized from CH2Cl2/n-hexane);
75% yield (0.264 g); mp 127 – 129 °C; Rf = 0.38 (2:1 n-
3.1.3. General procedure for synthesis of imidazoles
Two-necked flask attached with a condenser was charged with
formamide (50 mL), which was heated to 180 °C with stirring. A
solution of α-amino ketone in THF (15 mL) was then added
dropwise over 2 h using a syringe pump and the resulting mixture
was reacted for 6 h with stirring at 180 °C. After cooling, the
dark brown reaction mixture was treated with an equal volume of
water and 20 mL of 15 % aqueous NaOH. Then, the mixture was
extracted three times with Et2O, washed with brine, and dried
over Na2SO4. After filtration and concentration under reduced
pressure, the residue was purified by silica gel column
1
hexane/AcOEt); H NMR (300 MHz, CDCl3): δ = 7.74 (s, 1H),
7.34-7.25 (m, 8H), 7.16-7.09 (m, 3H), 6.97 (dd, J = 3.9, 1.2 Hz,
1H), 6.89 (t, J = 3.9 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ =
137.9, 137.1, 136.2, 134.6, 131.0, 129.5, 129.3, 128.6, 128.0,
127.6, 127.2, 125.5, 123.8, 122.8; HRMS (FAB): m/z [302.0878]
calcd. for C19H15N2S (M+H): 303.0956, found: 303.0972.

Dau, E. T. H.; Debitus, C.; Laurent, D.; Moriou, C.; Al-Mourabit,
A. Org. Lett., 2009, 11, 4874–4877.
3.1.3.6. 4-(4-Chlorophenyl)-1-(4-methoxyphenyl)-5-phenyl-1H-
imidazole (4h). 1-(4-Chlorophenyl)-2-(4-methoxyphenylamino)-
2-phenylethanone 3h (0.595 g, 1.70 mmol) was reacted with
formamide according to general procedure. White solid
(recrystallized from CH2Cl2/n-hexane); 52% yield (0.0319 g); mp
ACCEPTED MANUSCRIPT
3. Wang, X.-Q.; Liu, L.-X.; Y. Li, Y.; Sun, C.-J.; Chen, W.; Li, L.;
Zhang, L.-L.; Yang, X.-D. Eur. J. Med. Chem. 2013, 62, 111–121.
4. Khabnadideh, S.; Rezaei, Z.; Khalafi-Nezhad, A.; Bahrinajafi, R.;
Mohamadi, R.; Farrokhroz, A. A. Bioorg. Med. Chem. Lett. 2003,
13, 2863–2865.
5. Shingalapur, R. V.; Hosamani,K. M.; Keri, R. S. Eur. J. Med.
Chem. 2009, 44, 4244–4248.
6. Meer, L.; Janzer, R. C.; Kleihues, P.; Kolar, G. F. Biochem.
Pharmacol, 1986, 35, 3243–3247.
7. Gallagher, T. F.; Seibel, G. L.; Kassis, S.; Laydon, J. T.;
Blumenthal, M. J.; Lee, J. C.; Lee, D.; Boehm, J. C.; Fier-
Thompson, S. M.; Abt, J. W.; Soreson, M. E.; Smietana, J. M.;
Hall, R. F.; Garigipati, R. S.; Bender, P. E.; Erhard, K. F.; Krog,
A. J.; Hofmann, G. A.; Sheldrake, P. L.; McDonnell, P. C.;
Kumar, S.; Young, P. R.; Adams, J. L. Bioorg Med Chem Lett.
1997, 5, 49–64.
1
180 – 181 °C; Rf = 0.27 (2:1 n-hexane/AcOEt); H NMR (500
MHz, CDCl3): δ = 7.72 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.25-
7.30 (m, 3H), 7.21 (d, J = 8.6 Hz, 2H), 7.13 (dd, J = 6.6, 1.4 Hz,
2H), 7.03 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.79 (s,
3H); 13C NMR (125 MHz, CDCl3): δ = 159.1, 137.6, 137.5,
133.1, 132.3, 130.7, 129.9, 129.2, 128.6, 128.3, 128.2, 127.1,
114.3, 55.4; HRMS (FAB): m/z [360.1029] calcd. for
C22H18ClN2O (M+H): 361.1108, found: 361.1088.
8. Johnson, J. C.; Martinez, O.; Honko , A. N.; Hensley, L. E.;
Olinger, G. G.; Basler, C. F. Antiviral Res. 2014, 107, 102–109.
9. (a) Anderson, E. B.; Long, T. E. Polymer. 2010, 51, 2447–2454;
(b) Wang, Z.; Lu, P.; Chen, S.; Gao, Z.; Shen, F.; Zhang, W.; Xu,
Y.; Kwok, H. S.; Ma, Y. J. Mater. Chem. 2011, 21, 5451–5456.
10. (a) Herrmann, W. A.; Elison, M.; Fischer, J.; Kocher, C.; Artus, G.
R. J. Angew. Chem., Int. Ed. 1995, 37, 2371–2374; (b) Paris, E.
Chem. Rev. doi: 10.1021/acs.chemrev.6b00695.
3.1.3.7. 1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-5-phenyl-1H-
imidazole (4i). 2-(4-Chlorophenylamino)-1-(4-methoxyphenyl)-
2-phenylethanone 3i (0.440 g, 1.22 mmol) was reacted with
formamide according to general procedure. White solid
(recrystallized from CH2Cl2/n-hexane); 65% yield (0.144 g); mp
1
206 – 208 °C; Rf = 0.24 (2:1 n-hexane/AcOEt); H NMR (500
11. (a) Enders, D.; Balensiefer, T. Acc, Chem. Res. 2004, 37, 534–
541; (b) N-Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.;
WILEY-VCH GmbH & KGaA: Weinheim, 2006; (c) Marion, N.;
Die-Gonzale, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46,
2988–3000; (d) Enders, D.; Niemeier, O.; Henseler, A. Chem.
Rev. 2007, 107, 5606–5655; (e) Hopkinson, M. N.; Richter, C.;
Schedler, M.; Glorius, F. Nature. 2014, 510, 485–496; (f)
Flanigan, D. M.; Michailidis, F. R.; White, N. A.; Rovis, T. Chem.
Rev. 2015, 115, 9307−9387; Rajeev, S. M.; Akkattu, T. B.; Vijay,
N. Chem. Soc. Rev. 2015, 44, 5040−5052
MHz, CDCl3): δ = 7.73 (s, 1H), 7.45 (dt, J = 9.5, 2.6 Hz, 2H),
7.31-7.26 (m, 5H), 7.15-7.13 (m, 2H), 7.04 (dt, J = 9.5, 2.6 Hz,
2H), 6.80 (dt, J = 9.5, 2.6 Hz, 2H), 3.79 (s, 3H); 13C NMR (125
MHz, CDCl3): δ = 158.6, 139.1, 137.0, 135.1, 133.8, 130.8,
130.0, 129.4, 128.7, 128.4, 128.2, 127.6, 126.9, 113.7, 55.2;
HRMS (FAB): m/z [360.1029] calcd. for C22H18ClN2O (M+H):
361.1108, found: 361.1105.
12. Hama, Y. R.; Kim, S. H.; Shin,Y. J.; Lee, D. H.; Yang, M.; Min, J.
H.; Shin, J. S. Ind. Eng. Chem. 2010, 16, 556–559.
3.1.3.8.
1-(4-Chlorophenyl)-5-(naphthalen-2-yl)-4-phenyl-1H-
imidazole (4j). 2-(4-Chlorophenylamino)-2-(naphthalene-2-yl)-1-
phenylethanone 3j (0.417 g, 1.20 mmol) was reacted with
formamide according to general procedure. White solid
(recrystallized from CH2Cl2/n-hexane); 53% yield (0.241 g); mp
13. (a) Welton, T. Chem. Rev. 1999, 99, 2071–2083; (b) Rogers, R.
D.; Voth, G. A. Acc. Chem. Res. 2007, 40, 1077–1078; (c) Han,
X.; Armstrong, D. W. Acc. Chem. Res. 2007, 40, 1079–1086; (d)
Giernoth, R. Angew. Chem., Int. Ed. 2010, 49, 5608–5609.
14. Bredereck. H.; Theilig. G. Chem. Ber. 1953, 86, 88–96.
15. Sorrello, T. N.; Allen,W. E. J. Org. Chem. 1994, 59, 1589-1590.
16. Chen, C,-Y.; Hu, W.-P.; Yan, P.-C.; Senadi, G. C.; Wang, J.-J.
Org. lett. 2013, 15, 6116–6119.
17. Tong, S.; Wang, Q.; Wang, M.-X.; Zhu, J. Angew. Chem. Int. Ed.
2015, 54, 1293–1297.
18. Kamijo, S.; Yamamoto, Y. Chem. Asian. J. 2007, 2, 568 –578.
19. Yugandar, S.; Konda, S.; Parameshwarappa, G.; Ila, H. J. Org.
Chem. 2016, 81, 5606–5622.
1
249 – 251 °C; Rf = 0.37 (2:1 n-hexane/AcOEt); H NMR (500
MHz, CDCl3): δ = 7.84-7.75 (m, 3H), 7.68-7.65 (m, 2H), 7.55-
7.45 (m, 4H), 7.28-7.17 (m, 6H), 7.08 (dt, J = 9.4, 2.6 Hz, 2H);
13C NMR (125 MHz, CDCl3): δ = 139.6, 137.4, 135.0, 134.2,
133.9, 133.2, 132.8, 130.2, 129.5, 128.5, 128.4, 128.3, 128.1,
128.0, 127.7, 127.2, 126.89, 126.86, 126.7, 126.4; HRMS (FAB):
m/z [380.1080] calcd. for C25H18ClN2 (M+H): 381.1159, found:
381.1178.
20. Suzuki, Y.; Bakar, A.; Tanoi, T.; Nomura, N.; Sato, M.
Tetrahedron. 2011, 67, 4710–4715.
21. Huang, W. S.; Yuan, C. Y.; Wang, Z. Q. J. Fluorine. Chem. 1995,
74, 247–250.
22. Sato, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Tetrahedron.
2004, 60, 7899–7906.
23. Zhdankin, V. V. Chem. Rev. 2002, 102, 2523–2584.
24. Gu, L.; Liu, J.; Zhang, H. Chin. J. Chem. 2014, 32, 1267–1270.
25. Miyashita, A.; Matsuda, H.; Higashino, T. Chem. Pharm. Bull.
1992, 10, 2627–2631.
26. Hahnvajanawong, V.; Waengdongbung, W.; Theramongkol, P.
Orient. J. Chem. 2016, 32, 219–225.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from The Ministry of
Education, Culture, Sports, Science and Technology, Japan.
27. Chen, C,-Y.; Hu, W.-P.; Yan, P.-C.; Senadi, G. C.; Wang, J.-J.
Org. lett. 2013, 15, 6116 –6119.
Supplementary Material
References and notes
1. Lamberth, C.; Dinges, J. In Bioactive Heterocyclic compound
classes: Pharmaceuticals; Wiley-VCH: Germany, 2012; Vol. 1,
pp 3–20.
Supplementary data related to this article can be found at.
2. (a) Waton, N. G. Br. J. Pharmacol. Chemother. 1956, 11, 119–
127. (b) Arnstein, H. R. V.; White, A. M. Ann. NY. Acad. Sci.,
1964, 112, 807–822. (c) Walker, R. P.; Faulkner, D. J.; Engen, D.
V.; Clardy, J. J. Am. Chem. Soc., 1981, 103, 6772–6773. (d)
Appenzeller, J.; Tilvi, S.; Martin, M.; Gallard, J.; El-bitar, H.;