A greener route for the one-pot synthesis of 1,2,4,5-tetraarylated imidazoles

Article abstract of DOI:10.1007/s00706-012-0724-6

An efficient synthesis of various tetraarylated imidazoles using anhydrous FePO4 as a catalyst by fourcomponent condensation of benzil (or benzoin), aldehydes, amines, and ammonium acetate in refluxing ethanol is described. Springer-Verlag 2012.

Full text of DOI:10.1007/s00706-012-0724-6

Monatsh Chem (2012) 143:1529–1532
DOI 10.1007/s00706-012-0724-6
ORIGINAL PAPER
A greener route for the one-pot synthesis of 1,2,4,5-tetraarylated
imidazoles
•
Farahnaz K. Behbahani Talayeh Yektanezhad
Received: 18 May 2011 / Accepted: 13 January 2012 / Published online: 4 February 2012
Ó Springer-Verlag 2012
Abstract An efficient synthesis of various tetraarylated
imidazoles using anhydrous FePO4 as a catalyst by four-
component condensation of benzil (or benzoin), aldehydes,
amines, and ammonium acetate in refluxing ethanol is
described.
of 1,2,4,5-tetraarylated imidazoles are carried out by four-
component condensation of a 1,2-diketone or b-hydroxy-
ketone with an aldehyde, primary amine, and ammonium
acetate using microwaves [17], molecular iodine [18],
HClO4–SiO2 [19], heteropolyacid [20, 21], silica gel/
NaHSO4 [22], L-proline [23], FeCl3Á6H2O [24], BF3ÁSiO2
[25], and silica-supported Wells–Dawson acid [26]. In
addition, they can also be accessed by the condensation of
a 1,2-diketone with an aryl nitrile and primary amine under
microwave irradiation [27], by hetero-Cope rearrangement
[28], and by N-alkylation of triarylated imidazoles [29].
These methods are suitable for certain synthetic conditions;
however, many of these procedures are associated with one
or more disadvantages such as expensive reagents, longer
reaction times, tedious work-up procedure, low selectivity,
and large amounts of catalysts which would eventually
result in the generation of large amounts of toxic waste.
In this paper we present a novel, mild, and efficient
method for the synthesis of tetraarylated imidazoles using
benzil (or benzoin), aldehyde, aniline, and ammonium
acetate in the presence of FePO4 as a catalyst (Scheme 1).
Benzoin participated in the condensation with aldehyde,
amine, and ammonium acetate in the presence of FePO4 to
give the corresponding tetraarylated imidazoles, but the
yields were found to be low (20–40%). The role of FePO4
is probably in promoting the aerial oxidation of benzoin to
benzil [30], followed by formation of tetraarylated imida-
zoles in low yield.
Keywords 1,2,4,5-Tetraarylated imidazoles Á
Iron(III) phosphate Á One-pot synthesis
Introduction
The imidazole ring system is one of the most important
substructures found in a large number of natural products
and pharmacologically active compounds [1–5], and
members of this class of compounds are known to inhibit
NO synthase and have antifungal, antimycotic, antibiotic,
antiulcerative, antibacterial, antitumor, and CB1 receptor
antagonistic activities [6, 7]. Various substituted imida-
zoles act as inhibitors of p38 MAP kinase [8] and B-Raf
kinase [9], glucagon receptor antagonists [10], plant growth
regulators [11, 12], therapeutic agents [1], and also pesti-
cides [13, 14]. Accordingly, a number of synthetic methods
have been reported for the construction of this important
structure. In 1882, Radziszewski [15] and Japp and Rob-
inson [16] reported the first synthesis of highly substituted
imidazoles from 1,2-dicarbonyl compounds, different
aldehydes, and ammonia.
A number of methods have been also developed for the
synthesis of 1,2,4,5-tetraarylated imidazoles. The syntheses
In addition to the cases mentioned above, FePO4 is a
relatively cheap, safe, and available reagent [31] that has
also been employed for the selective oxidation of CH4 to
CH3OH [32] and benzene to phenol [33], one-pot synthesis
of dihydropyrimidinones and -thiones [34], and as a cata-
lyst in the synthesis of triarylated imidazoles [35].
Therefore, in connection with our research [36–38] on the
F. K. Behbahani (&) Á T. Yektanezhad
Department of Chemistry, Karaj Branch,
Islamic Azad University, Karaj, Iran
e-mail: Farahnazkargar@yahoo.com
123

1530
F. K. Behbahani, T. Yektanezhad
Scheme 1
development of simple and efficient methods for the syn-
thesis of various heterocyclic compounds, herein we
present iron(III) phosphate as a green, reusable, recyclable,
environmentally safe, inexpensive, and commercial cata-
lyst for the synthesis of 1,2,4,5-tetraarylated imidazoles.
Table 1 Catalytic activity evaluation for the synthesis of 1,2,4,5-
tetraphenylimidazole (4a)
Entry
FePO4/mol%
Time/h
Yield/%
1
2
3
4
5
0
5
24
10
8
10
75
80
90
91
7
Results and discussion
10
15
5
4.5
The typical procedure for preparing 1,2,4,5-tetraarylated
imidazoles involves heating a mixture of ammonium ace-
tate (ammonia source) in an ethanolic solution of benzil,
benzaldehyde, and aniline, and this system was used as a
model reaction to optimize the reaction conditions. Among
the tested catalysts, 10 mol% FePO4 promoted the facile
formation of product 4a in high yield (Table 1).
Table 2 Synthesis of 1,2,4,5-tetraphenylimidazole (4a) in the pres-
ence of FePO4 in ethanol at different temperatures
Entry
Temp/°C
Time/h
Yield/%
1
2
3
25
50
80
24
10
5.0
30
50
90
The four-component condensation of benzil, benzalde-
hyde, aniline, and ammonium acetate was also performed
in the absence of FePO4 under reflux; however, the yield of
4a was low (10%).
catalyst. The yields of products (4a–4j) obtained were good
to excellent without formation of any side products such as
2,4,5-triarylated imidazoles, oxidized products of anilines,
aldehydes etc., which are normally observed under the
influence of strong acids. The results obtained with
the current method are listed in Table 3. In each case, the
reaction profile is clean and this one-pot, four-component
procedure presents some improvements and advantages
over existing methods. One of the major advantages is the
isolation and purification of the products, which are
achieved by simple washing and crystallization of the
crude products.
The effect of temperature was investigated by carrying
out the model reaction in ethanol and at different temper-
atures in the presence of this catalyst (room temperature,
50 °C, and 80 °C). The results Table 2 show that the yield
increased as the reaction temperature was raised. There-
fore, all reactions were carried out in refluxing ethanol.
To explore the applicability of this method, the same
reaction conditions were applied to the synthesis of 1,2,4,5-
tetraarylated imidazoles via the one-pot, four-component
condensation of benzil (or benzoin) (1 mmol), aldehyde
(1 mmol), primary arylamine (1 mmol), and ammonium
acetate (1 mmol) as depicted in Scheme 1.
A plausible mechanism [39] for the synthesis of the
tetraarylated imidazoles involves the formation of inter-
mediate A by the reaction of a FePO4-activated aldehyde
[35], primary amine, and ammonium acetate (Scheme 2).
Intermediate A condenses with benzil to form intermediate
B, which in turn liberates a water molecule to form the
tetraarylated imidazole.
The substrate scope of the reaction was then evaluated
using a variety of structurally diverse aldehydes and pri-
mary arylamines (Table 3). The cyclocondensation of
benzyl or benzoin with various aromatic aldehydes bearing
electron-withdrawing groups (such as nitro) or electron-
releasing groups (such as methyl, hydroxyl, mono- or
dimethoxy groups), substituted anilines, and ammonium
acetate was carried out in the presence of FePO4 as a
To check the reusability of the catalyst, the condensation
of benzaldehyde, benzil, aniline, and NH4OAc to provide
123

A greener route for the one-pot synthesis of 1,2,4,5-tetraarylated imidazoles
1531
Table 3 Synthesis of 1,2,4,5-tetraarylated imidazoles using benzil (or benzoin), ammonium acetate, aromatic aldehydes, and arylamines
catalyzed by 10 mol% FePO4 (see Scheme 1)
Product
R1
R2
Time/h
Yield/%
Benzoin
M.p./°C
Benzoin
Benzil
Benzil
Found (reported)
4a
4b
4c
4d
4e
4f
H
H
5.5
8.5
8.5
8
5
40
30
35
30
20
25
40
40
30
25
90
90
96
94
88
90
85
86
90
82
218–219 (219–220 [21])
160–162 (155–157 [21])
223–225 (218–220 [21])
150–152 (151–153 [21])
254–256 (256–259 [21])
254–256 (–)
4-CH3
3-NO2
4-NO2
4-N(CH3)2
2-CH3
2-CH3O
2-CH3
4-OH
H
7
4-CH3
4-CH3
H
8
7.5
7
7.5
6.5
5.5
5.5
6.5
7.5
4-CH3
4-CH3O
4-CH3O
4-CH3
4-CH3
6
4g
4h
4i
5
164–166 (–)
5
256–257 (–)
6
303–305 (280 [21])
229–230 (230–232 [21])
4j
3-OH
7
Experimental
NH4OAc
NH2
FePO4
Ph
O
N
Melting points were measured by using the capillary tube
method with an Electrothermal 9200 apparatus. IR spectra
were recorded on a Perkin Elmer FT-IR spectrometer
scanning between 4,000 and 400 cm-1. The products were
characterized by 1H NMR and 13C NMR spectra recorded on
a Bruker DRX-300 NMR instrument. GC/MS spectra were
recorded on an Agilent 6890 GC Hp-5 (capillary 30 m 9
530 lm 9 1.5 lm, operating at 70 eV). Anhydrous FePO4
and the other starting materials were purchased from Merck.
All melting points compared satisfactorily with those
reported in the literature [21].
H
H
+ NH3
PhNH2
+
H
- H2O
A
Ph
Ph
O
- H2O
O
Ph
N
Ph
Ph
H
N
- H2O
N
Ph
HO
N
Ph
Ph
B
Preparation of 1,2,4,5-tetraarylated imidazoles: typical
procedure
Scheme 2
A 50-cm3 round-bottom flask was charged with benzil (or
benzoin) (2 mmol), aromatic aldehyde (2 mmol), aniline
(2 mmol), ammonium acetate (2 mmol), and FePO4
(10 mol%) followed by 5 cm3 of ethanol. The mixture was
then stirred and refluxed until the reaction was completed
(TLC). The mixture was then cooled to room temperature
and filtered to remove and recover the catalyst. The filtrate
was dried to afford crude product. The crystalline pure
product was obtained by further recrystallization from
water/ethanol (10:1).
the tetraarylated imidazoles under the conditions described
with FePO4 as a catalyst was run for four consecutive
cycles. The corresponding imidazole was obtained in 90,
88, 85, and 83% isolated yields, which proved the effi-
ciency of the catalyst for multiple usages.
Conclusion
1-(2,4-Dimethylphenyl)-2-(4-methylphenyl)-4,5-diphenyl-
1H-imidazole (4f, C30H26N2)
This method not only affords the products in excellent
yields but also avoids the problems associated with catalyst
cost, handling, safety, and pollution. FePO4 is an eco-
friendly catalyst for a variety of organic transformations. It
is nonvolatile, recyclable, nonexplosive, easy to handle,
and thermally robust. In view of the emerging importance
of this heterogeneous catalyst, we aim to explore the use of
FePO4 as a recyclable catalyst for the synthesis of other
five- and six-membered heterocyclic compounds.
Yield 90%; IR (KBr): vꢀ = 3,062 (C–H), 1,603 (C=C),
1,580 (C=N) cm-1; 1H NMR (300 MHz, CDCl3): d = 2.34
(s, 3H, CH3), 2.42 (s, 3H, CH3), 2.64 (s, 3H, CH3),
7.26–7.35 (m, 17H, Ar) ppm; 13C NMR (75 MHz, CDCl3):
d = 144.2 (N–C=N), 138.5, 136.0, 135.0, 131.5, 129.0,
127.5, 126.0, 124.5, 123.0, 122.2 (Ar, C=C), 24.5, 17.5,
15.3 (CH3) ppm; GC-MS: m/z (%) = 414 (3).
123

1532
F. K. Behbahani, T. Yektanezhad
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2-(2-Methoxyphenyl)-1-(4-methoxyphenyl)-4,5-diphenyl-
1H-imidazole (4g, C29H24N2O2)
Yield 85%; IR (KBr): vꢀ = 3,062 (C–H), 1,601 (C=C),
1,583 (C=N) cm-1; 1H NMR (300 MHz, CDCl3): d = 3.42
(s, 3H, OCH3), 3.71 (s, 3H, OCH3), 6.62–6.64 (d, 2H, Ar,
J = 8.8 Hz), 6.69–6.72(d, 1H, Ar, J = 8.3 Hz), 6.83–6.86
(d, 2H, Ar, J = 8.8 Hz), 6.97–7.02 (dd, 1H, Ar, J =
7.5,7.8 Hz), 7.13–7.26 (m, 11H, Ar), 7.29–7.37 (dd, 1H,
Ar, J = 7.8, 7.5 Hz) ppm; 13C NMR (75 MHz, CDCl3):
d = 159.5 (CH3O–C), 144.2 (N–C=N), 138.5, 137.0,
135.5, 129.0, 127.0, 125.0, 123.0, 122.0, 121.0, 115.0,
114.0 (Ar, C=C), 56.2 (CH3O) ppm; GC/MS: m/z (%) =
432 (3).
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Yield 86%; IR (KBr): vꢀ = 3,061 (C–H), 1,603 (C=C),
1,581 (C=N) cm-1; 1H NMR (300 MHz, CDCl3): d = 2.09
(s, 3H, CH3), 3.70 (s, 3H, OCH3), 6.61–6.64 (d, 2H, Ar,
J = 8.6 Hz), 6.79–6.82 (d, 2H, Ar, J = 8.9 Hz), 7.12–7.58
(m, 14H, Ar) ppm; 13C NMR (75 MHz, CDCl3): d = 160.5
(CH3O–C), 144.2 (N–C=N), 138.5, 136.0, 130.0, 129.0,
127.0, 126.0, 125.0, 123.0, 122.0, 115.2 (Ar, C=C), 56.2
(CH3O), 17.5 (CH3) ppm; GC/MS: m/z (%) = 416 (2).
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