Indium trifluoride: A highly efficient catalyst for the synthesis of fluorine-containing 2,4,5-trisubstituted imidazoles under solvent-free conditions

Article abstract of DOI:10.1016/j.jfluchem.2012.06.013

A new green protocol has been developed for the synthesis of fluorine containing 2,4,5-trisubstituted imidazoles via one-pot, three-component condensation reaction of 4,4-difluorobenzil with aldehydes and ammonium acetate using reusable indium (III) fluor

Full text of DOI:10.1016/j.jfluchem.2012.06.013

Journal of Fluorine Chemistry 142 (2012) 45–51
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Indium trifluoride: A highly efficient catalyst for the synthesis of
fluorine-containing 2,4,5-trisubstituted imidazoles under solvent-free conditions
*
Mudumala Veeranarayana Reddy, Yeon Tae Jeong
Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history:
A new green protocol has been developed for the synthesis of fluorine containing 2,4,5-trisubstituted
imidazoles via one-pot, three-component condensation reaction of 4,4-difluorobenzil with aldehydes
and ammonium acetate using reusable indium (III) fluoride (InF3) as Lewis acid catalyst under solvent-
free conditions. This protocol provides a novel and improved method for obtaining fluorine containing
2,4,5-trisubstituted imidazoles in terms of good yields with little catalyst loading.
ß 2012 Elsevier B.V. All rights reserved.
Received 13 April 2012
Received in revised form 12 June 2012
Accepted 13 June 2012
Available online 21 June 2012
Keywords:
Fluorine containing 2,4,5-trisubstituted
imidazoles
Indium fluoride
4,4-Difluorobenzil
Solvent-free reaction
1. Introduction
Imidazole and their derivatives, which usually possess diverse
biological activities, play important roles as versatile building
Fluorine-containing heterocycles are widely recognized as
important organic molecules showing interesting biological
activities with potential for applications in the medicinal and
agricultural fields [1–5]. Particularly fluorine has played an
important and historical role in the development of antipsychotic
drugs [2]. Fluorine substitution is often used as a strategy to
increase metabolic stability [3]. Introduction of fluorine-contain-
ing nitrogen heterocycles can bring about remarkable changes in
the physical, chemical and biological properties [4,5] of drugs.
Thus, fluorosubstituted nitrogen containing heterocycles posses-
sing anticardiovascular diseases, DPP-IV inhibitory activity,
herbicidal activity, anti-bacterial and anti-inflammatory activities
[6–8] as well as efficacy in anticancer [9] and antagonists for
paralyzing action of anti-diabetic activity [7]. Other beneficial
properties related to fluorine substitution, such as increased blood
brain barrier (BBB) permeability due to changes in lipophilicity or
amine pKa, are reasons that fluorinated drugs have been especially
important in CNS active drugs [10]. Consequently, the develop-
ment of novel synthetic methods for their synthesis has attracted
sustained interest in organic synthesis. In recent years, a number of
researches have been reported about the development of new
methodologies for syntheses of various kinds of fluorine-contain-
ing heterocycles [11–13].
blocks for the synthesis of natural products and as therapeutic
agents [14,15]. In particular, 2,4,5-trisubstituted imidazoles are
biologically active and occur in structures of a number of anti-
inflammatory [16], anti-allergic [17], analgesic [18] and glucagon
receptor antagonism [19]. This core also has been utilized in
diverse pharmaceutical applications such as anti-tumor [20] and
anti-thrombotic [21] activities agents. Recently, some imidazole
derivatives have been investigated for their piezochromism,
photochromism and thermochromism properties, and the results
reported suggest potential applications in molecular photonics and
sensing [22]. Therefore, the synthesis of these imidazole deriva-
tives has attracted much attention in organic synthesis.
In the last decade numerous methods have been developed for
the synthesis of highly substituted imidazoles by using various
catalytic systems including silica gel or Zeolite HY [23], silica gel/
NaHSO4 [24], molecular iodine [25], K5CoW12O40Á3H2O [26],
heteropolyacids [27], HClO4–SiO2 [28], Yb(OTf)3 [29], L-proline
[30], BF3–SiO2 [31], and silica-supported Wells–Dawson acid [32].
They can also be obtained by use of microwave irradiation [33] and
refluxing in acetic acid [34], silica sulfuric acid [35], NiCl2Á6H2O/
Al2O3 [36], ZrCl4 [37], ionic liquids [38], CAN [39] and
Cu(NO3)2Ázeolite [40]. Moreover, the syntheses of these heterocy-
clic compounds have been usually carried out in polar solvents
such as ethanol [27], methanol [30], acetic acid [34] and DMF [20]
leading to complex isolation and recovery procedures. However,
many of the methods reported above suffer from one or more
disadvantages such as the use of expensive moisture sensitive
* Corresponding author. Tel.: +82 51 629 6411; fax: +82 51 629 6408.
E-mail address: ytjeong@pknu.ac.kr (Y.T. Jeong).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.06.013

46
M. Veeranarayana Reddy, Y.T. Jeong / Journal of Fluorine Chemistry 142 (2012) 45–51
F
Table 1
F
Influence of different catalysts on the reaction of 4,4-difluorobenzil with 2-fluoro-4-
methoxybenzaldehyde and ammonium acetate.a
O
O
InF3
Entry
Catalyst
Amount
(mol%)
Time
Yieldb (%)
N
+R CHO
+
NH4OAc
(3)
Solvent-Free
(min)
R
N
H
60
C
F
1
2
3
4
5
No Catalyst
GaCl3
–
500
200
40
Trace
50
F
TiO2-SiO2
Cu(OSO2CF3)-SiO2
p-TSA polymer-
supported
Li(OTf)
75
(1)
(2a-p)
(4a-p)
60
76
180
55
Scheme 1. Synthesis of fluorine containing 2,4,5-trisubstituted imidazoles
catalyzed by InF3 under solvent-free condition.
6
7
120
130
90
60
Zn(O2CCH3)2
Nano Cu2O
InF3
70
8
65
metallic reagents, longer reaction times, tedious separation
procedures, and large amount of catalyst loadings which in turn
results in the generation of huge amount of metal wastes into the
environment. Hence, the development of clean safe, effective,
economical, high yielding and mild environmental benign proto-
cols is still desirable and is in demand.
It is evident from the recent literature that Indium (III) fluoride
(InF3) has invoked enormous interest as a green and potential
Lewis acid catalyst to construct carbon–carbon and carbon–
heteroatom bonds in various organic transformations [41–43].
Despite its great importance, only a few papers are reported on its
catalytic application in organic synthesis [41–43]. In combination
with the use of Lewis acid catalyst in organic transformations,
solvent-free methodologies for the synthesis of organic com-
pounds have attracted much interest because of their ease of
experimental procedures as well as work-up, low cost, clean,
efficient, environmentally benign, and high yielding processes. We
therefore became interested in devising more general and green
methods for the synthesis of fluorine containing 2,4,5-trisubsti-
tuted imidazoles derivatives.
9
2
40
80
10
11c
InF3
5
25
85
InF3
10
20
92, 90,
88, 85
a
Reaction conditions: 4,4-difluorobenzil (1 mmol), 2-fluoro-4-methoxybenzal-
dehyde (1 mmol) and ammonium acetate (2.2 mmol); temperature:60 8C.
b
Isolated yields.
c
Reusable catalyst.
summarized in Table 1. Besides this, we observed that the
concentration of the catalyst played a major role in catalyzing
the condensation reaction for the synthesis of fluorine containing
2,4,5-trisubstituted imidazoles. Using a model reaction as de-
scribed above and varying just the concentration of InF3 from
2 mol% to 10 mol%, the yield of product was increased from 85% to
92%. This shows that 10 mol% of InF3 is the suitable choice for the
optimum reaction rate and yield of fluorine containing 2,4,5-
trisubstituted imidazoles (Table 1, entries 9–11).
Next, the effect of temperature was also evaluated for the model
reaction. It was observed that fast reaction occurred on raising the
temperature from 20 8C to 60 8C and the yield of desired product
increased considerably. We were pleased to find that the reaction
proceeded smoothly and almost complete conversion of reactants
was observed at 60 8C to afford the desired product (4a) in 92%
yield within 20 min (Table 2). However, at room temperature a
lower yield of product was obtained even after longer reaction
times. With the optimistic results in hand, we chose a variety of
structurally diverse aromatic aldehydes to understand the scope
and efficiency of the InF3 promoted synthesis of fluorine containing
2,4,5-trisubstituted imidazoles.
It was observed that a wide variety of aldehydes (both aromatic
and aliphatic) and 4,4-difluorobenzil (1) to establish the scope of
this catalytic transformation (Table 3). A broad range of aromatic
aldehydes bearing electron donating and electron withdrawing
substituents underwent this one-pot, three-component cyclocon-
densation to furnish fluorine containing 2,4,5-trisubstituted
imidazoles in high yields. Aliphatic aldehydes afforded the
corresponding imidazoles in moderate yields. Various functional
groups were found to be compatible under the reaction conditions.
In general, the reactions were clean and no side products were
detected. In all cases, the reactions proceeded efficiently at 60 8C in
solvent-free and 10 mol% catalyst conditions.
Our literature survey at this stage revealed that there are no
reports on the synthesis of fluorine containing 2,4,5-trisubstituted
imidazoles under solvent-free at 60 8C mediated by InF3. Our main
target is to develop a green organic reaction methodology, which is
relatively faster and cleaner than conventional reactions.
2. Results and discussion
As a part of our continuing studies in developing efficient
synthetic methodologies [44,45] in organic preparations, we found
that the synthesis of fluorine containing 2,4,5-trisubstituted
imidazoles derivatives via a one-pot, three-component condensa-
tion reaction of 4,4-difluorobenzil (1) with aldehydes (2a–p)
ammonium acetate (3) can be efficiently achieved without any
solvent with the use of indium fluoride (InF3) under mild
conditions at 60 8C (Scheme 1). To optimize the reaction
conditions, we first examined the reaction of 4,4-difluorobenzil
(1, 1 mmol), 2-fluoro-4-methoxybenzaldehyde (2d, 1 mmol), and
ammonium acetate (3, 2.2 mmol) at 60 8C without catalyst under
solvent-free conditions in order to recognize the capability of the
catalyst. The reaction did not proceed even after prolonged
reaction time and no desired product was formed which supported
the catalytic activity of InF3. When the reaction was performed in
the presence InF3, it proceeded effectively to produce the desired
product (4d) in high yields. Some other Lewis acid catalysts such as
GaCl3, TiO2–SiO2, Cu(OSO2CF3)–SiO2, p-TSA polymer-supported,
Li(OTf), Zn(O2CCH3)2, and Nano Cu2O exhibited moderate to good
catalytic properties. In most of these cases comparative yields of
the desired product were obtained. Following the InF3-catalyzed
procedure, the reported methods required expensive catalyst, toxic
or organic solvents, strong acidic conditions, high catalyst loading,
and long reaction times. These results clearly demonstrated that
InF3 is a more efficient catalyst for the synthesis of fluorine
containing 2,4,5-trisubstituted imidazoles. The results are
The reusability of the catalyst was also examined in the
synthesis of fluorine containing 2,4,5-trisubstituted imidazoles.
Table 2
Effect of temperature.a
Entry
Temperature (8C)
Time (min)
Yieldb (%)
1
2
3
20
40
60
200
60
20
65
92
20
a
Reaction conditions: 4,4-difluorobenzil (1 mmol), 2-fluoro-4-methoxybenzal-
dehyde (1 mmol) and ammonium acetate (2.2 mmol); different temperature.
b
Isolated yields.

M. Veeranarayana Reddy, Y.T. Jeong / Journal of Fluorine Chemistry 142 (2012) 45–51
47
Table 3
Synthesis of fluorine containing 2,4,5-trisubstituted imidazoles.a
Entry
1
Aldehyde
Product
Time (min)
22
Yieldb (%)
91
mp (8C)
150–152
F
CHO
F
F
N
Br
N
H
Br
2a
F
4a
2
25
90
156–158
F
CHO
Cl
F
Cl
F
N
2b
N
H
F
4b
3
20
92
232–234
F
CHO
F
N
Me
F
N
H
Me
2c
F
4c
4
20
92
250–252
F
CHO
F
F
N
OMe
N
H
OMe
CHO
2d
F
4d
5
26
89
175–177
F
NO2
O2N
N
F
N
H
F
2e
F
4e
6
24
88
192–194
CHO
F
F
F
F
N
F
2f
N
H
F
4f
7
24
90
210–212
F
CHO
F
F
N
F
N
H
F
2g
F
4g

48
M. Veeranarayana Reddy, Y.T. Jeong / Journal of Fluorine Chemistry 142 (2012) 45–51
Table 3 (Continued )
Entry
Aldehyde
Product
Time (min)
26
Yieldb (%)
91
mp (8C)
8
238–240
F
CHO
F
N
F
F
N
H
F
2h
F
4h
9
23
90
282–284
F
CHO
F
N
F
F
2i
N
H
F
F
4i
10
22
92
214–216
CHO
F
N
N
H
2j
F
4j
11
29
88
150–152
F
CHO
HO
OEt
OEt
N
N
N
H
2k
F
4k
12
28
87
220–222
F
CHO
OH
HO
N
Cl
N
H
2l
Cl
F
4l
13
25
92
216–218
O
O
F
OHC
O
O
N
N
H
2m
F
4m
14
26
90
247–249
F
CHO
N
S
2n
N
H
S
F
4n

M. Veeranarayana Reddy, Y.T. Jeong / Journal of Fluorine Chemistry 142 (2012) 45–51
49
Table 3 (Continued )
Entry
Aldehyde
Product
Time (min)
35
Yieldb (%)
84
mp (8C)
160–162
15
F
OHC
2o
N
N
H
F
4o
16
40
80
198–200
F
OHC
N
2p
N
H
F
4p
a
The 4,4-difluorobenzil (1 mmol), aldehydes (1 mmol) and ammonium acetate (2.2 mmol) using 10 mol% InF3 in solvent-free at 60 8C.
Isolated yields.
b
InF3
R
C
H
O
NH3
-H2o
F3In
F3In
F
F
F
F
F
F
F
C
H
R
InF3
O
HN
H
H
N
O
O
R
O
O
N
NH3
-H2o
InF3
R
N
NH
NH
H
F
F
F3In
OH
F
F
H
N
H
N
N
N
R
R
R
-H2o
-InF3
N
H
N
F
F
F
Scheme 2. A plausible mechanism for the formation of fluorine containing 2,4,5-trisubstituted imidazoles catalyzed.
The catalyst was recovered after each run, washed three times with
chloroform, dried in an oven at 100 8C, and tested for its activity in
subsequent runs. It was found that the catalyst could be reused
four times without the loss of activity (Table 1, 11). The structures
of all the newly synthesized compounds were established by their
1H, 13C, 19F & NMR and HRMS, ESI-MS analyses.
A mechanism for the catalytic activity of InF3 in the synthesis of
fluorine containing 2,4,5-trisubstituted imidazoles should be postu-
lated as shown in Scheme 2. The InF3 probably induces polarization of
carbonyl group in aldehydes as well as in benzil. The nucleophilic
attack of the nitrogen of ammonia obtained from ammonium acetate,
one-pot, three-component condensation reaction of 4,4-difluor-
obenzil with aldehydes and ammonium acetate, Indium fluoride as
a novel, efficient, and recyclable catalyst. The salient features of
this protocol are high product yields, shorter reaction time,
solvent-free condition, low catalyst loading, and relatively mild
acid catalyst with easy work-up procedure, which make this
procedure quite simple, more convenient, and environmentally
benign. Hopefully, our methodology could be a valid contribution
to the existing processes in the field of fluorine containing 2,4,5-
trisubstituted imidazoles synthesis.
on activated carbonyl, results the formation of aryl aldimine and
a-
4. Experimental
iminokeone. Their subsequent reaction followed by intramolecular
interaction leads to cyclization. Eventually to the formed intermediate
dehydrates to give the fluorine containing 2,4,5-trisubstituted
imidazoles (4a–p) in excellent yields.
4.1. Method and apparatus
Chemicals were purchased from Aldrich and Alfaaesar Chemical
Companies. NMR spectra were recorded in ppm in DMSO-d6 on a
JEOL JNM ECP 400 NMR instrument using TMS as internal standard.
Mass spectra were recorded on a JEOL JMS-700 mass spectrometer.
All melting points were determined using open capillaries on an
Electrothermal-9100 (Japan) instrument.
3. Conclusion
In conclusion, we have developed a solvent-free reaction for the
synthesis of fluorine containing 2,4,5-trisubstituted imidazoles via

50
M. Veeranarayana Reddy, Y.T. Jeong / Journal of Fluorine Chemistry 142 (2012) 45–51
4.2. Synthesis of fluorine containing 2,4,5-trisubstituted imidazoles
123.8, 118.2, 115.7; 19F NMR (376 MHz, DMSO-d6):
d
À109.12 (m,
2F), À113.32 (m, 1F); HRMS (ESI, m/z): calcd for C21H12F3N3O2
A mixture of 4,4-difluorobenzil (1 mmol), aldehydes (1 mmol),
ammonium acetate (2.2 mmol) and InF3 (10 mol%) was stirred at
60 8C under solvent-free condition for appropriate time (Table 3).
The progress of the reaction was monitored by TLC. After
completion of the reaction, the mixture was washed with
chloroform and filtered to recover the catalyst. The filtrate was
evaporated, and the crude product was recrystallized from ethanol
to afford pure fluorine containing 2,4,5-trisubstituted imidazoles
in good to excellent yields.
(M+H+) 395.0882, found: 395.0870.
4.2.6. 2-(2,3-Difluorophenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole
(4f)
White solid; Mp: 192–194 8C. 1H NMR (400 MHz, DMSO-d6):
d
12.01 (s, 1H), 8.09–8.01 (m, 4H), 7.80 (t, J = 8.0 Hz, 2H), 7.64 (t,
J = 8.0 Hz, 1H) 7.50–7.42 (m, 2H), 7.33–722 (m, 2H); 13C NMR
(100 MHz, DMSO-d6):
d 164.2 (d, JC–F = 255.1 Hz), 162.0 (C–F, d,
1J = 244.0 Hz), 160.4 (C–F, d, 1J = 243.0 Hz), 152.2, 148.2, 144.3,
132.4, 130.2, 129.8, 129.1, 128.0, 122.6, 117.3, 115.5; 19F NMR
4.2.1. 2-(4-Bromo-2-fluorophenyl)-4,5-bis(4-fluorophenyl)-1H-
(376 MHz, DMSO-d6):
d
À99.53 (m, 1F), À109.70 (m, 2F), À112.88
imidazole (4a)
(m, 1F); HRMS (ESI, m/z): calcd for C21H12F4N2 (M+H+) 368.0937,
White solid; Mp: 150–152 8C. 1H NMR (400 MHz, DMSO-d6):
d
found: 368.0927.
12.2 (s, 1H), 8.05–8.01 (q, 4H), 7.96 (t, J = 8.2 Hz, 2H), 7.81 (dd,
J = 2.5, 10.2 Hz 1H), 7.56–7.46 (m, 2H), 7.30 (t, J = 8.0 Hz, 1H); 13C
4.2.7. 2-(2,4-Difluorophenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole
NMR (100 MHz, DMSO-d6):
d
162.0 (C–F, d, 1J = 244.5 Hz), 161.7
(4g)
(C–F, d, 1J = 242.0 Hz), 158.8 (d, JC–F = 255.1 Hz), 145.4, 134.9,
White solid; Mp: 210–212 8C. 1H NMR (400 MHz, DMSO-d6):
d
133.1, 131.8, 130.2, 129.0, 125.4, 121.2, 120.2, 119.2, 116.6; 19F
12.60 (s, 1H), 8.10–8.04 (q, 4H), 7.64 (t, J = 8.2 Hz, 2H), 7.57–7.40
(m, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.36 (t, J = 8.3 Hz, 1H), 7.12 (d,
NMR (376 MHz, DMSO-d6):
d
À109.92 (m, 2F), À113.73 (m, 1F);
HRMS (ESI, m/z): calcd for C21H12BrF3N2 (M+H+) 428.0136, found:
J = 8.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
d 163.5 (dd, JC–
428.0140.
F = 247.1, 9.2 Hz), 162.2 (C–F, d, 1J = 244.0 Hz), 161.3 (C–F, d,
1J = 242.0 Hz), 159.2 (dd, JC–F = 251.1, 10.1 Hz), 147.0, 133.6, 132.2,
130.1, 129.6, 122.6, 119.2, 116.1, 112.2, 105.2; 19F NMR (376 MHz,
4.2.2. 2-(2-Chloro-6-fluorophenyl)-4,5-bis(4-fluorophenyl)-1H-
imidazole (4b)
DMSO-d6):
d
À109.26 (m, 2F), À114.58 (m, 1F), À116.25 (m, 1F);
White solid; Mp: 156–158 8C. 1H NMR (400 MHz, DMSO-d6):
d
MS (ESI): m/z 368 (M+).
12.5 (s, 1H), 8.15–8.11 (m, 4H), 7.69–7.63 (q, 4H), 7.31–7.20 (m,
3H); 13C NMR (100 MHz, DMSO-d6):
d
162.8 (C–F, d, 1J = 244.3 Hz),
4.2.8. 2-(3,4-Difluorophenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole
(4h)
161.7 (C–F, d, 1J = 242.5 Hz), 158.2 (d, JC–F = 250.1 Hz), 148.0, 136.9,
134.6, 131.2, 129.8, 128.6, 125.1, 123.2, 122.1, 116.3, 112.3; 19F
White solid; Mp: 238–240 8C. 1H NMR (400 MHz, DMSO-d6):
d
NMR (376 MHz, DMSO-d6):
d
À109.96 (m, 2F), À112.27 (m, 1F);
13.01 (s, 1H), 8.07–8.02 (m, 4H), 7.70–7.46 (m, 5H), 7.34–7.29 (m,
HRMS (ESI, m/z): calcd for C21H12ClF3N2 (M+H+) 384.0641, found:
2H); 13C NMR (100 MHz, DMSO-d6): 162.7 (C–F, d, 1J = 244.2 Hz),
d
384.0637.
161.2 (C–F, d, 1J = 242.0 Hz), 150.2 (dd, JC–F = 251.5, 9.2 Hz), 148.3,
145.5, 135.2, 133.2, 130.9, 129.8, 127.5, 125.2, 119.2, 117.5, 115.4;
4.2.3. 2-(3-Fluoro-4-methylphenyl)-4,5-bis(4-fluorophenyl)-1H-
19F NMR (376 MHz, DMSO-d6):
d
À109.80 (m, 2F), À114.39 (m, 1F),
imidazole (4c)
À116.40 (m, 1F); MS (ESI): m/z 368 (M+).
White solid; Mp: 232–234 8C. 1H NMR (400 MHz, DMSO-d6):
d
11.7 (s, 1H), 8.02–7.96 (m, 4H), 7.80 (d, J = 8.2 Hz, 2H), 7.50 (d,
J = 8.2 Hz 1H), 7.24 (t, J = 8.0 Hz, 2H), 7.12–7.08 (m, 2H), 2.30 (s,
4.2.9. 2-(3,5-Difluorophenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole
(4i)
3H); 13C NMR (100 MHz, DMSO-d6):
d
163.0 (C–F, d, 1J = 244.0 Hz),
White solid; Mp: 340–342 8C. 1H NMR (400 MHz, DMSO-d6):
d
162.5 (d, JC–F = 249.7 Hz), 161.4 (C–F, d, 1J = 242.0 Hz), 148.8, 136.9,
12.90 (s, 1H), 8.01–7.96 (q, 4H), 7.74 (d, J = 8.2 Hz, 2H), 7.68 (d,
J = 8.2 Hz, 2H), 7.54 (t, J = 8.3 Hz, 1H), 7.29–7.25 (m, 2H); 13C NMR
133.9, 131.2, 129.2, 128.2, 125.6, 124.6, 120.6, 118.2, 114.6, 13.9;
19F NMR (376 MHz, DMSO-d6):
d
À114.51 (m, 2F), À118.17 (m, 1F);
(100 MHz, DMSO-d6): d 166.8 (d, JC–F = 255.1 Hz), 162.0 (C–F, d,
HRMS (ESI, m/z): calcd for C22H15F3N2 (M+H+) 364.1187, found:
1J = 244.7 Hz), 161.4 (C–F, d, 1J = 241.0 Hz), 145.9, 137.1, 134.9,
364.1189.
130.2, 129.8, 128.1, 125.4, 115.6, 108.1; 19F NMR (376 MHz, DMSO-
d6):
d
À109.23 (m, 2F), À114.12 (m, 1F), À116.72 (m, 1F); MS (ESI):
4.2.4. 2-(2-Fluoro-4-methoxyphenyl)-4,5-bis(4-fluorophenyl)-1H-
m/z 368 (M+).
imidazole (4d)
White solid; Mp: 250–252 8C. 1H NMR (400 MHz, DMSO-d6):
d
4.2.10. 4,5-Bis(4-fluorophenyl)-2-(4-isopropylphenyl)-1H-imidazole
13.0 (s, 1H), 8.14–8.10 (q, 4H), 7.90–782 (m, 2H), 7.69–7.20 (m,
(4j)
3H), 6.76 (d, J = 8.0 Hz, 2H), 3.69 (s, 3H); 13C NMR (100 MHz,
White solid; Mp: 214–216 8C. 1H NMR (400 MHz, DMSO-d6):
12.55 (s, 1H), 8.08 (d, J = 7.8 Hz, 4H), 7.59–7.47 (m, 2H), 7.35–7.29
(q, 4H), 7.16–7.03 (q, 2H), 3.03–2.96 (m, 1H), 1.25 (d, J = 6.4 Hz,
d
DMSO-d6):
d
162.6 (C–F, d, 1J = 244.0 Hz), 161.4 (C–F, d,
1J = 242.0 Hz), 159.3 (d, JC–F = 255.8 Hz), 158.2, 149.4, 136.2,
133.8, 131.2, 130.2, 129.8, 116.6, 112.7, 106.2, 102.2, 55.4; 19F
1H); 13C NMR (100 MHz, DMSO-d6): 163.0 (C–F, d, 1J = 244.0 Hz),
d
NMR (376 MHz, DMSO-d6):
d
À114.36 (m, 2F), À117.75 (m, 1F);
162.5 (C–F, d, 1J = 242.0 Hz), 150.1, 145.3, 137.9, 134.2, 130.9,
HRMS (ESI, m/z): calcd for C22H15F3N2O (M+H+) 380.1136, found:
129.8, 128.0, 124.2, 116.5, 39.0, 23.4, 20.7; 19F NMR (376 MHz,
380.1138.
DMSO-d6):
C
d
À112.67 (m, 2F); HRMS (ESI, m/z): calcd for
24H20F2N2 (M+H+) 374.1595, found: 374.1580.
4.2.5. 2-(4-Fluoro-2-nitrophenyl)-4,5-bis(4-fluorophenyl)-1H-
imidazole (4e)
4.2.11. 2-(4,5-Bis(4-fluorophenyl)-1H-imidazol-2-yl)-5-
(diethoxyamino)phenol (4k)
White solid; Mp: 175–177 8C. 1H NMR (400 MHz, DMSO-d6):
d
11.90 (s, 1H), 8.09–8.01 (m, 5H), 7.80 (t, J = 8.2 Hz, 2H), 7.54–7.45
White solid; Mp: 150–152 8C. 1H NMR (400 MHz, DMSO-d6):
d
(m, 2H), 7.35–730 (m, 2H); 13C NMR (100 MHz, DMSO-d6):
d
162.8
12.95 (s, 1H), 9.50 (s, 1H), 8.09–8.06 (m, 4H), 7.80–7.25 (m, 7H),
(C–F, d, 1J = 244.0 Hz), 161.5 (C–F, d, 1J = 242.5 Hz), 160.2 (d, JC–
3.61–3.55 (q, 4H), 1.08 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz,
F = 248.5 Hz), 150.2, 149.2, 136.3, 133.2, 131.9, 130.7, 129.8, 125.5,
DMSO-d6): d
162.3 (C–F, d, 1J = 244.3 Hz), 161.4 (C–F, d,

M. Veeranarayana Reddy, Y.T. Jeong / Journal of Fluorine Chemistry 142 (2012) 45–51
51
1J = 242.0 Hz), 153.6, 151.4, 147.2, 135.2, 131.5, 130.9, 129.6, 128.0,
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126.7, 122.4, 119.5, 118.6, 116.5, 58.5, 14.5; 19F NMR (376 MHz,
DMSO-d6):
d
À112.17 (m, 2F); MS (ESI): m/z 451 (M+).
4.2.12. 2-(4,5-Bis(4-fluorophenyl)-1H-imidazol-2-yl)-4-
chlorophenol (4l)
White solid; Mp: 220–222 8C. 1H NMR (400 MHz, DMSO-d6):
d
12.50 (s, 1H), 9.25 (s, 1H), 8.14–8.10 (m, 4H), 7.80–7.31 (m, 7H);
13C NMR (100 MHz, DMSO-d6):
d
162.6 (C–F, d, 1J = 243.5 Hz),
161.4 (C–F, d, 1J = 241.8 Hz), 151.8, 148.8, 134.5, 132.5, 130.9,
129.6, 128.1, 126.4, 119.6, 115.8, 111.1; 19F NMR (376 MHz,
DMSO-d6):
C
d
À110.25 (m, 2F); HRMS (ESI, m/z): calcd for
21H13ClF2N2O (M+H+) 382.0684, found: 382.0697.
4.2.13. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-bis(4-
fluorophenyl)-1H-imidazole (4m)
White solid; Mp: 216–218 8C. 1H NMR (400 MHz, DMSO-d6):
d
12.80 (s, 1H), 8.10–8.02 (m, 4H), 7.57–7.48 (m, 3H), 7.22 (t,
J = 8.2 Hz, 2H), 6.95 (d, J = 8.2 Hz, 2H), 3.95 (s, 4H); 13C NMR
(100 MHz, DMSO-d6):
1J = 242.1 Hz), 152.2, 145.2, 143.8, 134.2, 132.2, 129.8, 124.4, 122.8,
d
162.2 (C–F, d, 1J = 244.0 Hz), 161.0 (C–F, d,
117.6, 113.8, 109.3, 64.2; 19F NMR (376 MHz, DMSO-d6):
d
À110.21
(m, 2F); HRMS (ESI, m/z): calcd for C23H16F2N2O2 (M+H+) 390.118,
found: 390.110.
4.2.14. 4,5-Bis(4-fluorophenyl)-2-(thiophen-3-yl)-1H-imidazole (4n)
White solid; Mp: 247–249 8C. 1H NMR (400 MHz, DMSO-d6):
d
12.25 (s, 1H), 8.09–8.01 (q, 4H), 7.82–7.30 (m, 7H); 13C NMR
(100 MHz, DMSO-d6):
163.0 (C–F, d, 1J = 244.5 Hz), 161.9 (C–F, d,
d
1J = 241.9 Hz), 148.2, 137.8, 134.2, 132.9, 130.2, 129.8, 128.6, 127.8,
126.9, 117.8; 19F NMR (376 MHz, DMSO-d6):
(ESI): m/z 338 (M+).
d
À110.53 (m, 2F); MS
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Catalysis A: Chemical 266 (2007) 109–113.
4.2.15. 4,5-Bis(4-fluorophenyl)-2-propyl-1H-imidazole (4o)
White solid; Mp: 160–162 8C. 1H NMR (400 MHz, DMSO-d6):
d
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541–544.
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2575–2577.
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635–641.
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699–702.
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Chemical 263 (2007) 279–281.
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2991–3000.
12.09 (s, 1H), 8.16–8.13 (m, 4H), 7.69–7.30 (m, 4H), 2.20–1.68 (m,
4H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6):
d 162.0
(C–F, d, 1J = 244.0 Hz), 161.4 (C–F, d, 1J = 242.0 Hz), 148.6, 133.2,
130.9, 130.0, 129.1, 117.5, 32.5, 21.2, 14.3; 19F NMR (376 MHz,
DMSO-d6):
d
À111.01 (m, 2F); MS (ESI): m/z 298 (M+).
4.2.16. 4,5-Bis(4-fluorophenyl)-2-isopropyl-1H-imidazole (4p)
White solid; Mp: 198–200 8C. 1H NMR (400 MHz, DMSO-d6):
d
12.80 (s, 1H), 8.10 (d, J = 8.2 Hz, 4H), 7.50–7.42 (m, 4H), 3.18–3.10
(m, 1H), 1.25(d, J = 7.2 Hz, 6H); 13C NMR (100 MHz, DMSO-d6)
d:
162.5 (C–F, d, 1J = 244.8 Hz), 161.4 (C–F, d, 1J = 241.9 Hz), 146.2,
133.5, 130.4, 129.7, 128.2, 115.5, 33.2, 21.3, 20.7; 19F NMR
(376 MHz, DMSO-d6):
C
d
À110.42 (m, 2F); HRMS (ESI, m/z): calcd for
18H16F2N2 (M+H+) 298.1282, found: 298.1284.
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Sciences 5 (2008) 463–467.
Acknowledgement
[40] K. Sivakumar, A. Kathirvel, A. Lalitha, Tetrahedron Letters 51 (2010) 3018–3021.
[41] M. Sridhar, M. Kishore Kumar Reddy, C. Narsaiah, B. China Ramanaiah, V.
VenkataSairam, Tetrahedron Letters 53 (2012) 697–701.
[42] L. Teck-Peng, X. Kai-Chen, H. Diana Sook-Chiang, S. Keng-Yeow, Synlett (1998)
369–370.
This research work was supported by the second stage of BK21
Program.
[43] B.P. Bandgar, K.A. Shaikh, Journal of Chemical Research 1 (2004) 34–36.
[44] M. Veeranarayana Reddy, S.D. Dindulkar, Y.T. Jeong, Tetrahedron Letters 52
(2011) 4764–4767.
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