Tributylhexadecylphosphonium bromide: An efficient reagent system for the one-pot synthesis of 2,4,5-trisubstituted imidazoles

Article abstract of DOI:10.1515/hc-2014-0182

The reaction of benzil, an aromatic aldehyde, and ammonium acetate in ethanol at reflux in the presence of tributylhexadecylphosphonium bromide as catalyst affords a 2,4,5-trisubstituted imidazole. The present methodology offers several advantages over the literature methods, including excellent yields, shorter reaction times, environmentally benign milder reaction conditions, cost-effectiveness of catalyst, easy workup, and purification of products by nonchromatographic methods.

Full text of DOI:10.1515/hc-2014-0182

Heterocycl. Commun. 2015; 21(2): 73–76
Mohammad Heidari, Mohsen Rezaei and Rashid Badri*
Tributylhexadecylphosphonium bromide: an
efficient reagent system for the one-pot synthesis
of 2,4,5-trisubstituted imidazoles
Abstract: The reaction of benzil, an aromatic aldehyde, in photography, modular of glucagon receptors, plant
and ammonium acetate in ethanol at reflux in the pres- growth regulators, and therapeutic agents [6–10].
ence of tributylhexadecylphosphonium bromide as cata-
Imidazole derivatives are most generally prepared by
lyst affords a 2,4,5-trisubstituted imidazole. The present ring construction. One synthetic methodology reported in
methodology offers several advantages over the litera- literature involves ring formation by condensation of an
ture methods, including excellent yields, shorter reaction aldehyde, ammonium acetate, and a 1,2-diketone in the
times, environmentally benign milder reaction conditions, presence of a catalyst such as silica sulfuric acid, InCl3,
cost-effectiveness of catalyst, easy workup, and purifica- Al2O3, acetic acid, ZrCl4 or NiCl2 [9–12]. Other methods,
tion of products by nonchromatographic methods.
especially for the synthesis of 2,4,5-trisubstituted imida-
zoles, may involve the use of ionic liquids [13–15]. Most
Keywords: 2,4,5-trisubstituted imidazoles; aldehyde; existing methods, however, suffer from several drawbacks,
benzil; homogeneous catalysis; one-pot synthesis.
including low yields, formation of by-products, laborious
and complex workup, tedious purification, and the use
of strong acidic conditions. In this report, we describe a
new method that produces a variety of 2,4,5-trisubstituted
imidazoles unambiguously, under mild conditions and in
good yields.
DOI 10.1515/hc-2014-0182
Received October 11, 2014; accepted February 2, 2015; previously
published online March 26, 2015
Introduction
Results and discussion
Multicomponent reactions (MCRs) are very important In the preliminary experiments, the condensation of
and useful processes in organic synthesis, especially in benzil (1, 1 mmol), ammonium acetate (2 mmol), and
medicinal and heterocyclic chemistry. In these simple and benzaldehyde (2a, 1 mmol) in the absence of a catalyst in
efficient processes that demonstrate high atom economy ethanol at ambient temperature and under reflux condi-
and simple procedures [1, 2], usually three or more reac- tions was attempted. These experiments produced no
tants are mixed together in a simple vessel to produce new expected imidazole product 3a (Scheme 1).
compounds that contain portions of all the components.
In the presence of 5 mol% of tributylhexadecylphos-
The use of MCRs for synthesis of imidazole and its deriva- phonium bromide (TBHDPB) in the absence of any solvent
tives has attracted much interest [3–5]. Many derivatives
of imidazole are known as fungicides and herbicides,
inhibitors of p38 MPA kinase, light-sensitive materials
Ph
Ph
O
O
Ph
Ph
N
TBHDPB
NH4OAc
RCHO
2
R
EtOH, ∆, 45–120 min
N
H
1
3a-n
*Corresponding author: Rashid Badri, Department of Chemistry,
College of Science, Ahvaz Branch, Islamic Azad University, Ahvaz,
Iran, e-mail: r.badri@khouzestan.srbiau.ac.ir;
rashidbadri@yahoo.com
Mohammad Heidari: Department of Chemistry, College of Science,
Ahvaz Branch, Islamic Azad University, Ahvaz, Iran
Mohsen Rezaei: Department of Toxicology and Pharmacology,
School of Pharmacy, Jundishapur University of Medical Sciences,
Ahvaz, Iran
3a: R = Ph
3h: R = 4-Cl-C6H4
3i: R = 2-Cl-C6H4
3j: R = 4-Br-C6H4
3k: R = 4-O2N-C6H4
3l: R = 3-O2N-C6H4
3m: R = Et
3b: R = 4-Me-C6H4
3c: R = 4-Me2N-C6H4
3d: R = 4-MeO-C6H4
3e: R = 3,4-diMeO-C6H3
3f: R = 4-HO-C6H4
3n: R = Me
3g: R = 3-HO-C6H4
Scheme 1:ꢀ
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ꢁM. Heidari et al.: Tributylhexadecylphosphonium bromide
H
NH
NH3
-H2O
NH2
OH
NH2
NH2
14
P+
H
A
14
Ph
Ph
O
1 4
P+
O
P+
O
HO
Ph
Ph
H
N
H
H
N
H
HO
NH3
-2H2O
Ph
Ph
N
N
H
NH4OAc
Ph
Ph
N
N
H
B
[1-5]-H shift
Scheme 2:ꢀA plausible mechanism for the formation of 2,4,5 trisubstituted imidazole.
at 60°C after 3 h of heating, the reaction produced com- the products make the method attractive for the synthesis
pound 3a in 30% yield. Then the reaction was conducted of various 2,4,5-trisubstituted imidazoles.
with varying amounts of the catalyst and in various sol-
vents. Under optimal conditions, the reaction was con-
ducted in ethanol under reflux conditions for 1 h and gave
Experimental
85% of the desired product 3a. The remaining products
of Scheme 1 were obtained under these optimized con-
All products were characterized by comparison of their physical and
ditions. The reaction tolerates electron-donating groups
on the aromatic aldehyde to give products 3 in excellent
yields. Only good yields are obtained for nitro-substituted
benzaldehydes, and even lower yields are observed for ali-
phatic aldehydes.
1
spectral data (mp, H NMR and IR) with those of authentic samples.
Melting points were determined in open glass capillaries on a Met-
tler FP51 melting point apparatus and are uncorrected. The progress
of the reactions was followed by thin-layer chromatography (TLC)
analysis using silica gel SILG/UV 254 plates.
A mechanism for the catalytic activity of TBHDPB in
the synthesis of trisubstituted imidazole is postulated
in Scheme 2. It is suggested that the TBHDPB catalyst
facilitates the formation of diamine intermediate A by
increasing the electrophilicity of the carbonyl group of the
aldehyde. Condensation of intermediate product A with
benzil followed by elimination of water leads to conjugate
intermediate B, which in turn undergoes rearrangement
to the trisubstituted imidazole by a [1, 5] hydrogen shift.
General procedure for the synthesis of 2,4,5-trisubstituted
imidazoles 3a-n
A mixture of benzil (1 mmol), TBHDPB (0.051 g, 0.1 mmol, 10 mol%),
and aldehyde (1 mmol) and ammonium acetate (2 mmol) in ethanol
(10 mL) was stirred under reflux for 45–120 min. Afer the completion
of reaction, as monitored by TLC analysis, the mixture was cooled
to room temperature, diluted with water, and extracted with ethyl
acetate. Organic layer was dried over anhydrous MgSO4, and then
solvent was removed under reduced pressure. Crude product was
washed with n-hexane and crystallized from ethanol to obtain the
pure product in 30–98% yield.
Conclusion
This report describes a simple and efficient one-pot multi-
component methodology for the synthesis of 2,4,5-trisub-
stituted imidazoles catalyzed by 10 mol% TBHDPB. The
2,4,5-Triphenyl-1H-imidazole (1a)ꢀReaction time 1 h; pale yellow
powder; yield 85%; mp 268–270°C (mp 267–269°C) [16].
4,5-Diphenyl-2-p-tolyl-1H-imidazole (1b)ꢀReaction time 45 min;
availability of the reagent, easy workup, and good yield of white powder; yield 89%; mp 232–234°C (mp 233–235°C) [16].
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[4-(4,5-Diphenyl-1H-imidazol-2-yl)phenyl]dimethylamine
(1c)ꢀReaction time 45 min; pale yellow powder; yield 92%; mp 257–
259°C (mp 256–259°C) [16].
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2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (1d)ꢀReaction
time 45 min; pale yellow powder; yield 98%; mp 230–231°C (mp,
231–233°C) [17].
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4-(4,5-Diphenyl-1H-imidazol-2-yl)phenol (1f)ꢀReaction time 50
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3-(4,5-Diphenyl-1H-imidazol-2-yl)phenol (1g)ꢀReaction time 50
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2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (1h)ꢀReaction
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2-(2-Chlorophenyl)-4,5-diphenyl-1H-imidazole
(1i)ꢀReaction
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2-(4-Bromophenyl)-4,5-diphenyl-1H-imidazole (1j)ꢀReaction time
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Acknowledgments: We are thankful to Islamic Azad
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