A facile strategy for the synthesis of highly substituted imidazole using tetrabutyl ammoniumbromide as catalyst

Article abstract of DOI:10.1007/s11164-011-0352-5

A simple and facile strategy for the synthesis of highly substituted imidazoles has been developed by multi-component condensation of 1,2-diketone, aldehyde, amine, and ammonium acetate in presence of tetrabutyl ammonium bromide as catalyst. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0352-5

Res Chem Intermed (2012) 38:359–365
DOI 10.1007/s11164-011-0352-5
A facile strategy for the synthesis of highly substituted
imidazole using tetrabutyl ammoniumbromide
as catalyst
•
C. Kurumurthy G. Santhosh Kumar
•
•
•
•
G. Malla Reddy P. Nagender P. Shanthan Rao
B. Narsaiah
Received: 26 May 2011 / Accepted: 16 July 2011 / Published online: 26 August 2011
Ó Springer Science+Business Media B.V. 2011
Abstract A simple and facile strategy for the synthesis of highly substituted
imidazoles has been developed by multi-component condensation of 1,2-diketone,
aldehyde, amine, and ammonium acetate in presence of tetrabutyl ammonium
bromide as catalyst.
Keywords 1,2-Diketone Á Aldehyde Á Amine Á Multi-component condensation Á
Tetrabutyl ammonium bromide Á Ammonium acetate/ammonium formate
Introduction
The modern trend in synthetic organic chemistry is driving more towards multi-
component reactions (MCRs) because of several advantages over linear reactions in
synthesis of complex molecules in single step with high yields and simplified isolation
procedures. The imidazole nucleus is present in large number of natural products and
also in pharmacologically active compounds [1–5]. Therefore, the interest is
continuously growing on synthesis of imidazole derivatives and a number of synthetic
methods are available in literature. In 1882, Radziszewski reported the first synthesis
of highly substituted imidazoles from 1,2-diketone, different aldehydes and ammonia
[6, 7]. Specifically, synthesis of 1,2,4,5-tetrasubstituted imidazoles are accomplished
by multi-component condensation of 1,2-diketone, aldehyde, primary amine and
ammonium acetate using molecular iodine [8], FeCl3Á6H2O [9], BF3.SiO2 [10],
Silicagel/NaHSO4 [11], Silicagel or zeolite HY [12], HClO4-SiO2 [13], Silica-
supported acid [14], heteropolyacid [15], K5CoW12O40Á3H2O [16], L-proline [17],
C. Kurumurthy Á G. Santhosh Kumar Á G. Malla Reddy Á P. Nagender Á
P. Shanthan Rao Á B. Narsaiah (&)
Fluoroorganic Division, Indian Institute of Chemical Technology, Tarnaka,
Hyderabad 500607, India
e-mail: narsaiah_1984@yahoo.co.in; narsaiah@iict.res.in
123

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C. Kurumurthy et al.
and microwaves [18]. Similarly, 2,4,5-trisubstituted imidazoles are made from three
component condensation of 1,2-diketone, aldehyde and ammonium acetate using
silica sulfuric acid [19], NiCl2Á6H2O/Al2O3 [20], CAN [21], ZrCl4 [22], ionic liquids
[23], acetic acid [24–26], and microwaves [27–30]. Metal nitrate over zeolite HY [31],
and DABCO [32] was also used as catalysts for the synthesis of highly substituted
imidazoles. All the methods cited above have disadvantages in terms of cost,
hazardous nature, long reaction times, tedious isolation procedures and high loading of
catalyst. In recent past, tetrabutyl ammonium bromide (TBABr) has emerged as mild,
water-tolerant, inexpensive and environmentally compatible homogenous catalyst in
various organic transformations [23, 33–35]. Biginelly-type compounds [36] and
biscoumarine & 3,4-dihydropyrano[c]chromone derivatives [37] were also prepared
by using TBABr as catalyst. To the best of our knowledge, quarternary ammonium
salts more specifically tetrabutyl ammonium bromide (TBABr) is not been used as a
catalyst for the synthesis of highly substituted imidazoles and attracted our attention to
investigate the application of TBABr as a catalyst. Thus, a series of imidazole
derivatives were synthesized by using TBABr as catalyst and found to be more
efficient.
Results and discussion
In a typical reaction, benzaldehyde (1.0 mmol) was reacted with ammonium acetate
(2.0 mmol) and 1,2-diketone (1.0 mmol) in t-BuOH (5 mL) using tetrabutyl
ammonium bromide (TBABr, 10 mol%) as catalyst at 80 °C in 6–8 h and obtained
2,4,5-trisubstituted imidazole derivatives in high yield. Similar reaction was also
conducted in presence of ammonium formate or ammonium trifluoroacetate in place
of ammonium acetate and obtained imidazole products of marginally low yield. In
order to find an alternate catalyst, tetraethyl ammonium bromide (TEABr) used as
catalyst in 10 mol%, however, it was found to yield 80%. Further efforts were made
to identify a suitable solvent. Thus, solvents like acetonitrile, THF, methanol,
ethanol, isopropanol, t-BuOH and H2O was screened for the same reaction and
t-BuOH was found to be a good solvent with 95% yield (Table 1).
After having established the conditions with a choice of solvent, catalyst and
ammonium acetate, the scope of present protocol was extended using diverse
Table 1 Effect of solvent on yield of product
Entry
Solvent
Time (h)
Yield (%)
1.
2.
3.
4.
5.
6.
7.
CH3CN
THF
8
30
8
45
CH3OH
C2H5OH
(CH3)2CHOH
(CH3)3COH
H2O
8
65
8
72
8
89
8
95
10
No reaction
123

Synthesis of highly substituted imidazole
361
Br
N
CHO
Ph
Ph
O
N
Ph
NH4OAc
Ph
t-BuOH
80 oC
N
H
O
2eq
1eq
1eq
1
Scheme 1 Preparation of 2,4,5-trisubstituted imidazole derivatives
substituted aldehydes and obtained 2,4,5-trisubstituted imidazole derivatives in high
yields. The reaction details are drawn in a Scheme 1 and tabulated in Table 2.
Table 2 Preparation of 2,4,5-trisubstituted imidazoles
___________________________________________________________________________
Entry Aldehyde
Amine
source
1,2-diketone
Product
Yield (%)
___________________________________________________________________________
Ph
O
N
Ph
Ph
Ph
Ph
Ph
Ph
N
CHO
CHO
NH4OAc
H
O
O
1.
2.
95
91
O
O
N
Ph
Ph
N
H
HCOONH4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
Ph
N
CHO
CHO
CHO
CF3COONH4
H
O
3.
4.
5.
6.
7.
8.
85
O
N
Ph
Ph
N
Cl
Br
NH4OAc
H
Cl
O
89
O
O
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
H
NH4OAc
Br
O
O
88
85
N
F
CHO
NH4OAc
NH4OAc
NH4OAc
H
F
O
N
N
H
MeO
CHO
OMe
NO2
O
90
O
N
N
H
O2N
CHO
O
83
___________________________________________________________________________
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C. Kurumurthy et al.
Table 2 continued
___________________________________________________________________________
Ph
O
N
Ph
Ph
Ph
Ph
Ph
N
H
HO
CHO
CHO
NH4OAc
OH
F
O
O
9.
87
F
F
F
N
F
Ph
N
H
Ph
NH4OAc
O
F
10.
11.
75
Ph
Ph
F3C
O
CF3
N
Ph
Ph
N
CHO
CHO
NH4OAc
H
O
92
Ph
Ph
Ph
Ph
O
O
N
Ph
Ph
Ph
Ph
N
NH4OAc
NH4OAc
H
O
O
12.
13.
14.
88
89
N
N
CHO
CHO
H
O
S
O
S
Ph
Ph
O
N
Ph
Ph
N
NH4OAc
H
O
88
___________________________________________________________________________
Br
CHO
NH2
N
O
Ph
Ph
N
N
Ph
NH4OAc
1eq
Ph
t-BuOH
80oC
O
1eq
1eq
1eq
Scheme 2 Preparation of 1,2,4,5-tetrasubstituted imidazole derivatives
Similarly, 1,2,4,5-tetrasubstituted imidazoles were prepared by reaction of
benzaldehyde (1.0 mmol) with ammonium acetate (1.0 mmol), aniline (1.0 mmol)
and benzil (1.0 mmol) using TBABr (10 mol%) as catalyst in t-BuOH (5 mL) at
80 °C for 8 h and obtained the product. The same reaction was further extended
with substituted benzaldehydes and established the conditions. The synthetic
sequence is drawn in a Scheme 2 and products are tabulated in Table 3.
In conclusion, an efficient single pot strategy has been developed for the
preparation of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazole derivatives
using tetrabutyl ammonium bromide as a catalyst. The method is established with
123

Synthesis of highly substituted imidazole
363
Table 3 Preparation of 1,2,4,5-tetrasubstituted imidazoles
___________________________________________________________________________
Entry Aldehyde
Amine(1) Amine(2)
1,2-diketone
Product
Yield (%)
___________________________________________________________________________
Ph
N
Ph
N
O
Ph
Ph
NH2
CHO
NH4OAc
O
1.
2.
87
Ph
Ph
N
N
O
Cl
Ph
Ph
Cl
CHO
NH2
NH4OAc
O
80
Ph
Ph
N
N
O
O
F
Ph
Ph
F
NH2
CHO
NH4OAc
O
O
3.
4.
81
75
Ph
Ph
N
N
OMe
Ph
Ph
MeO
CHO
NH2
NH4OAc
Ph
Ph
N
N
F
O
NH2
F
Ph
Ph
Cl
CHO
CHO
NH4OAc
NH4OAc
Cl
O
5.
6.
78
80
Ph
Ph
N
O
Ph
N
Ph
NH2
O
Ph
___________________________________________________________________________
diverse functionalized aldehydes and applicable to the synthesis of desired
functional imidazoles.
Experimental
IR spectra were recorded on a Perkin-Elmer FT-IR 240-C spectrophotometer using
1
KBr optics. H NMR spectra were recorded on Bruker AV 300 MHz in DMSO
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C. Kurumurthy et al.
using TMS as internal standard. Electron impact (EI) and chemical ionization mass
spectra were recorded on a VG 7070 H instrument at 70 eV. All the reactions were
monitored by thin layer chromatography (TLC) on precoated silica gel 60 F254
(mesh); spots were visualized with UV light. Merck silica gel (60–120 mesh) was
used for column chromatography. CHN analyses were recorded on a vario EL
analyzer.
Synthesis of 2,4,5-tri substituted imidazole derinatives.
2,4,5-Triphenyl-1H-imidazole [32]
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole [31]
2-(4-Bromorophenyl)-4,5-diphenyl-1H-imidazole [32]
2-(4-Fluorophenyl)-4,5-diphenyl-1H-imidazole [32]
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole [31]
2-(4-Nitrophenyl)-4,5-diphenyl-1H-imidazole [31]
4-(4,5-Diphenyl-1H-imidazol-2-yl)phenol [32]
4,5-Diphenyl-2-(2,4,6-trifluorophenyl)-1H-imidazole.
I.R. (KBr, cm-1): 3422 (-NH-), 1620, 1540; 1H NMR (DMSO, 300 MHz):
d 7.09–7.18 (m, 1H, Ar–H), 7.23–7.35 (m, 6H, Ar–H), 7.49–7.55 (m, 4H, Ar–H),
7.99–8.08 (m, 1H, Ar–H), 12.62 (br-s, 1H, NH); MS (EI, 70 eV): m/z M?., 350,
165; Anal. Calcd. for C21H13F3N2 : C 71.99, H 3.74, N 8.00%. Found: C 71.45, H
3.52, N 8.11%.
4,5-Diphenyl-2-(2-(trifluoromethyl)phenyl)-1H-imidazole [38]
2-Cyclohexyl-4,5-diphenyl-1H-imidazole [39]
2-(Furan-2-yl)-4,5-diphenyl-1H-imidazole [31]
4,5-Diphenyl-2-(thiophen-2-yl)-1H-imidazole [39]
Synthesis of 1,2,4,5-tetra substituted imidazole derivatives
1,2,4,5-Tetraphenyl-1H-imidazole [32]
2-(4-Chlorophenyl)-1,4,5-triphenyl-1H-imidazole [31]
1-(3-Chloro-4-fluorophenyl)-2,4,5-triphenyl-1H-imidazole
I.R. (KBr, cm-1): 1600, 1530; 1H NMR (DMSO, 300 MHz): d 6.88–6.93 (m, 1H,
Ar–H), 7.02 (t, 1H, J = 8.49 Hz, Ar–H), 7.09–7.30 (m, 12H, Ar–H), 7.37–7.41 (m,
2H, Ar–H), 7.51 (d, 2H, J = 6.79 Hz, Ar–H); MS (EI, 70 eV): m/z M?., 424, 165;
Anal. Calcd. for C27H18ClFN2 : C 76.32, H 4.27, N 6.59%. Found: C 75.98, H 4.42,
N 6.50%.
2-(4-Methoxyphenyl)-1,4,5-triphenyl-1H-imidazole [31]
2-(4-Fluorophenyl)-1,4,5-triphenyl-1H-imidazole
1
I.R. (KBr, cm-1): 1598, 1495; H NMR (DMSO, 300 MHz): d 6.92 (t, 2H,
J = 8.68 Hz, Ar–H), 7.03–7.12 (m, 4H, Ar–H), 7.17–7.30 (m, 9H, Ar–H),
7.35–7.40 (m, 2H, Ar–H), 7.51 (d, 2H, J = 6.79 Hz, Ar–H); MS (EI, 70 eV): m/z
M?., 390, 165; Anal. Calcd. for C27H19FN2 : C 83.05, H 4.90, N 7.17%. Found: C
82.71, H 4.72, N 7.05%.
1-Benzyl-2,4,5-triphenyl-1H-imidazole [32]
Acknowledgment Authors are thankful to Director, IICT for his constant encouragement and Council
of Scientific and Industrial Research (CSIR), New Delhi for the grant of fellowship.
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Synthesis of highly substituted imidazole
365
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