Trichloroisocyanuric acid-catalyzed one-pot synthesis of 2,4,5-trisubstituted imidazoles

Article abstract of DOI:10.1007/s00706-012-0830-5

Trichloroisocyanuric acid was found to be a highly efficient homogeneous catalyst for synthesis of imidazoles via one-pot, three-component condensation of aldehydes with benzil and ammonium acetate. The valuable advantages of this method are high yields of products, easy work-up and purification procedure, and use of a commercially available, inexpensive, and non-volatile catalyst.

Full text of DOI:10.1007/s00706-012-0830-5

Monatsh Chem (2013) 144:387–390
DOI 10.1007/s00706-012-0830-5
ORIGINAL PAPER
Trichloroisocyanuric acid-catalyzed one-pot synthesis
of 2,4,5-trisubstituted imidazoles
•
Seyedeh Fatemeh Hojati Seyede Atefe Nezhadhoseiny
•
Zahra Beykzadeh
Received: 31 August 2011 / Accepted: 7 August 2012 / Published online: 6 September 2012
Ó Springer-Verlag 2012
Abstract Trichloroisocyanuric acid was found to be a
highly efficient homogeneous catalyst for synthesis of
imidazoles via one-pot, three-component condensation
of aldehydes with benzil and ammonium acetate. The
valuable advantages of this method are high yields of
products, easy work-up and purification procedure, and use
of a commercially available, inexpensive, and non-volatile
catalyst.
multi-component reactions [5]. The valuable imidazole
structure has been extensively found in many biologically
active natural products. Imidazole-containing compounds
have a wide variety of pharmaceutical properties. Imid-
azole is the main structural unit in some widely used
drugs, for example ketoconazole [6], omeprazole [7],
cimetidine [8], clotrimazole [9], and metronidazole [10].
which are antifungal, proton pump inhibitor, antiulcer-
ative, antibiotic, and antifungal. Furthermore, a variety of
substituted imidazoles are used as p38 Map kinase [11],
B-Raf kinase [12], and glucagon receptors [13], and as
plant growth regulators [14], pesticides [15], and anti-
bacterial [16], antitumor [17], and anti-inflammatory [18]
agents. They are also found in the structures of ionic
liquids [19, 20].
Keywords Trichloroisocyanuric acid Á Imidazoles Á
Three-component reaction Á Homogeneous catalyst
Introduction
Multi-component reactions have attracted much interest in
diverse areas of chemistry, particularly in modern organic
synthesis, because they are one-pot processes in which
three or more easily accessible components react to form a
single product [1–4]. Properties of multi-component
reactions include high flexibility, selectivity, and atom
economy. It has been proved that multi-component reac-
tion is a convenient and powerful tool for preparation of
some biologically and pharmaceutically active organic
compounds [3, 4]. Imidazoles are among the most
important classes of heterocycles that can be obtained by
Numerous methods have been developed for synthesis
of substituted imidazoles. 2,4,5-Trisubstituted imidazoles
can be prepared by three-component cycloaddition of a 1,2-
diketone, a-hydroxyketone, or a-ketomonoxime with an
aldehyde and ammonium acetate. This cyclocondensation
occurs in the presence of acetic acid [5], silica-supported
sulfuric acid [21], InCl3Á3H2O [22], ceric ammonium
nitrate [23], NiCl2Á6H2O/Al2O3 [24], and Yb(OTf)3 [25]
under reflux conditions. Ionic liquids [26] and ultrasonic
[27] and microwave irradiation [28] have been also used
for this purpose.
Although some of these methods for synthesis of
substituted imidazoles via three-component reactions are
useful, most suffer from one or more disadvantages, for
example harsh reaction conditions, complex work-up and
purification procedure, use of toxic and/or expensive metal
catalyst, and low yield of products. Therefore, development
of a mild and efficient method for synthesis of this valuable
heterocycle to overcome previous shortcomings is still a
serious challenge for organic chemists.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0830-5) contains supplementary
material, which is available to authorized users.
S. F. Hojati (&) Á S. A. Nezhadhoseiny Á Z. Beykzadeh
Department of Chemistry, Hakim Sabzevari University,
Sabzevar, Iran
e-mail: hojatee@yahoo.com
123

388
S. F. Hojati et al.
three-component synthesis of 2,4,5-trisubstituted imidazoles
in the presence of trichloroisocyanuric acid as homogeneous
catalyst.
Table 1 Optimization of the model reaction conditions
Results and discussion
Entry Catalyst (mol %)
NH4OAc/equiv. Solvent
Yield/%a
We started by optimizing the reaction conditions for con-
densation of benzaldehyde, benzil, and ammonium acetate
in the presence of TCCA in EtOH, as model reaction
(Table 1). Different molar ratios of substrates and catalyst
were investigated. The reaction was also performed in
different solvents, for example acetonitrile, dichlorometh-
ane, H2O, methanol, and toluene and in the absence of
solvent at room temperature and under reflux conditions.
The results are summarized in Table 1. As shown in
Table 1, the best result was obtained with benzaldehyde–
benzil–NH4OAc–TCCA in 1:1:7:0.2 molar ratio in ethanol
under reflux. 2,4,5-Triphenylimidazole was obtained in
90 % yield after 12 h (Table 1, entry 3). To show the effect
of TCCA in promotion of imidazole synthesis, the model
reaction was performed under optimized reaction condi-
tions but in the absence of catalyst, which led to very poor
yield (10 %) after 24 h (Table 1, entry 15). Similar
experiments were conducted to compare the catalytic
activity of TCCA with Lewis acids such as TiO2 and
BiNO3Á5H2O (Table 1, entries 16, 17). In addition, 1,3-
1
TCCA (20)
TCCA (20)
TCCA (20)
TCCA (20)
TCCA (5)
TCCA (10)
TCCA (30)
TCCA (20)
TCCA (20)
TCCA (20)
TCCA (20)
TCCA (20)
TCCA (20)
TCCA (20)
–
2
5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
5
2
25
90
90
30
50
60
3
7
4
10
7
5
6
7
7
7
8
7
CH3CN 50
9
7
CH2Cl2
MeOH
H2O
5
10
11
12
13
14b
15c
16
17
18
a
7
40
–
7
7
Toluene
–
–
7
10
30
10
–
7
EtOH
EtOH
EtOH
EtOH
EtOH
7
TiO2 (20)
7
BiNO3Á5H2O (20)
DBDMH (20)
7
25
10
7
The reaction was performed with benzaldehyde–benzil in 1:1 molar
ratio for 12 h under reflux
b
The reaction was performed at room temperature
c
Table 2 Three-component synthesis of imidazole derivatives cata-
lyzed by TCCA (Scheme 1)
The reaction mixture was heated under reflux for 24 h
Entry Ar
Yield/%a M.p./°C
Lit. m.p./°C
Trichloroisocyanuric acid (TCCA) is an N-halo com-
pound which was first synthesized in 1902 [29]. It has been
used primarily as disinfectant in swimming pools and as a
cleaning and sterilizing agent in bathrooms and for laundry
[30]. In recent years, TCCA has attracted much attention as
a homogeneous catalyst, because it is commercial avail-
ability, inexpensive, and non-volatile. It is known to be a
very useful chlorinating and oxidizing reagent and a highly
efficient catalyst in organic transformations [30]. TCCA is
an excellent promoter in the synthesis of xanthene deriv-
atives [31], the Biginelli reaction [32], electrophilic
substitution of indole [33], and trimethylsilylation [34] and
acylation [35] of alcohols.
1
C6H5
90
87
95
85
90
93
90
95
83
280–281 277–278 [37]
199–201 197.3–197.8 [38]
262–263 261–262 [36]
292–294 301–303 [39]
244–246 244–246 [36]
146–148 150 [40]
2
2-Cl–C6H4
4-Cl–C6H4
3-Br–C6H4
4-Br–C6H4
2-NO2–C6H4
3-NO2–C6H4
4-NO2–C6H4
2-CH3–C6H4
3
4
5
6
7
265–267 260 [25]
8
236–237 236–237 [36]
198–202 205–207 [38]
208–210 210–210.5 [38]
221–223 227–228 [36]
235–237 235–237 [36]
9
10
11
12
2-CH3O–C6H4 93
4-CH3O–C6H4 89
4-HO–C6H4
81
Because the development of new MCRs and improving
known MCRs are an interesting and ongoing area in
chemistry, we now report a simple and efficient method for
Products were identified by comparison of their physical and spectral
data with those of authentic samples
a
Isolated yields
Scheme 1
123

Trichloroisocyanuric acid catalyzed one-pot synthesis of 2,4,5-trisubstituted imidazoles
389
Scheme 2
dibromo-5,5-dimethylhydantoin, an N-halo organocatalyst,
was used in the model reaction (Table 1, entry 18). Among
these catalysts, TCCA was found to be the best choice for
the three-component synthesis of 2,4,5-substituted imida-
zoles, because of its high catalytic activity.
Experimental
All materials were commercial reagent grade and were
purchased from Merck. 1H and 13C NMR spectra were
recorded on a Bruker Avance 500 MHz spectrometer.
Melting points were taken on a Bamstead Electrothermal
apparatus. IR spectra were recorded on a Shimadzu FT-IR
8440S spectrophotometer. Elemental analysis was per-
formed using a Heraeus CHN-O-Rapid analyzer.
To show the applicability of the method, different aromatic
aldehydes were reacted with benzil and ammonium acetate in
the presence of TCCA under the optimized reaction condi-
tions. The corresponding 2,4,5-trisubstituted imidazoles were
obtained in good yields (Scheme 1; Table 2).
It is apparent from Table 2 that aldehydes with electron-
donating and electron-withdrawing substituents were con-
verted to the corresponding imidazoles in very good yields.
In all cases the profiles were clean and these three-com-
ponent reactions were satisfactorily performed without
significant amounts of side products. Use of only 20 mol %
TCCA is sufficient to promote the reaction and no Lewis
acid is necessary in the procedure.
General procedure for synthesis of 2,4,5-triaryl-1H-
imidazoles
In a round-bottomed flask (25 cm3) equipped with a
magnetic stirrer, a solution of aldehyde (1 mmol), benzil
(1 mmol), ammonium acetate (7 mmol), and TCCA
(0.2 mmol) in 5 cm3 ethanol was prepared and the mixture
was stirred for 12 h under reflux conditions (85 °C). The
progress of the reaction was monitored by TLC (n-hexane–
EtOAc 4:1). After completion of the reaction, the mixture
was poured into ice–water, resulting in a solid precipitate.
The resulting crude product was isolated by filtration,
dried, and washed with n-hexane to afford the corre-
sponding imidazole in good to excellent yield (Table 2).
Although the actual mechanism of the three-component
synthesis of 2,4,5-trisubstituted imidazoles catalyzed by
TCCA is unclear, a plausible mechanism for this reaction
may be postulated as shown in Scheme 2. First, TCCA
releases chloronium ions which activate both aldehyde and
benzil carbonyl groups. Nucleophilic attack of two mole-
cules of ammonium on the activated carbonyl group of
aldehyde B generates a diamine intermediate C. Conden-
sation of C with activated benzil E followed by
dehydration produces diimine F, and chloronium ions are
released to return to the next catalytic cycle. Finally, [1,5]
hydrogen shift of diimine intermediate F affords the
desired 2,4,5-trisubstituted imidazole G.
Acknowledgments The authors are grateful to the Research
Council of Hakim Sabzevari University for the financial support of
this work.
References
In conclusion we have developed a simple and highly
efficient one-pot three-component method for the synthesis
of 2,4,5-trisubstituted imidazoles catalyzed by TCCA. This
procedure has many attractive features, for example oper-
ational simplicity, high yield of products, and easy work-up
and purification. Furthermore, use of TCCA as a com-
mercially available, inexpensive, and non-volatile catalyst
makes the method environmentally friendly and economi-
cally acceptable.
1. Zhu J, Bienayme H (2005) Multicomponent reactions. Wiley–
VCH, Weinheim
2. Domling A (2006) Chem Rev 106:17
3. Weber L (2002) Drug Discov Today 7:143
4. Tempest PA (2005) Curr Opin Drug Discov Dev 8:776
5. Cook AH, Jones DG (1941) J Chem Soc 278
6. Heeres J, Backx LJJ, Mostmans JH, Van Cutsem J (1979) J Med
Chem 22:1003
7. Tanigawara Y, Aoyama N, Kita T, Shirakawa K, Komada F,
Kasuga M, Okumura K (1999) Clin Pharmacol Ther 66:528
123

390
S. F. Hojati et al.
8. Brimblecombe RW, Duncan WAM, Durant GJ, Cemmett JC,
23. Sangshetti JN, Kokare ND, Kotharkara SA, Shinde DB (2008) J
Chem Sci 120:463
24. Heravi MM, Bakhtiari K, Oskooie HA, Taheri S (2007) J Mol
Catal A Chemical 263:279
Ganellin CR, Parsons ME (1975) J Int Med Res 3:86
9. Dorneanu O, Popovici I, Boiculese L, Popovici I, Bosnea DJ
(2003) Preventive Med 11:41
10. Dinh HT, Kernbaum S, Frottier J (1978) Lancet 3111:338
11. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S,
Green D, McNulty D, Blumenthal MJ, Keys JR, Vatter SWL,
Strickler JE, Mclaughlin MM, Siemens IR, Fisher SM, Livi GP,
White JR, Adams JL, Young PR (1994) Nature 372:739
12. Takle AK, Brown MJ, Davies S, Dean DK, Francis G, Gaiba A,
Hird AW, King FD, Lovell PJ, Naylor A, Reith AD, Steadman
JG, Wilson DM (2006) Bioorg Med Chem Lett 16:378
13. de Laszlo SE, Hacker C, Li B, Kim D, MacCoss M, Mantalo N,
Pivnichny JV, Colwell L, Koch GE, Cascieri MA, Hagmenn WK
(1999) Bioorg Med Chem Lett 9:641
25. Wang LM, Wang YH, Tian H, Yao YF, Shao JH, Liu B (2006) J
Fluorine Chem 127:1570
26. Siddiqui SA, Narkhede UC, Palimkar SS, Daniel T, Loholi RJ,
Srinivasan KV (2005) Tetrahedron 61:3539
27. Khosropour AR (2008) Ultrason Sonochem 15:659
28. Balalaie S, Arabanian A (2000) Green Chem 2:274
29. Chattaway FD, Wadmore JM (1902) J Chem Soc 81:191
30. Kolvari E, Ghorbani-Choghamarani A, Salehi P, Shirini F, Zol-
figol MA (2007) J Iran Chem Soc 4:126
31. Bigdeli MA, Nemati F, Mahdavinia GH, Doostmohammadi H
(2009) Chin Chem Lett 20:1275
14. Schmierer R, Mildenberger H, Buerstell H (1987) German Patent
361464; (1988) Chem Abstr 108:37838
32. Bigdeli MA, Jafari S, Mahdavinia GH, Hazarkhani H (2007)
Catal Commun 8:1641
15. Maier T, Schmierer R, Bauer K, Bieringer H, Buerstell H, Sachse
B (1989) US Patent 4820335; (1989) Chem Abstr 111:19494W
16. Antolini M, Bozzoli A, Ghiron C, Kennedy G, Rossi T, Ursini A
(1999) Bioorg Med Chem Lett 9:1023
33. Veisi H, Gholbedaghi R, Malakootikhah J, Sedrpoushan A,
Maleki B, Kordestani D (2010) J Heterocycl Chem 47:1398
34. Khazaei A, Zolfigol MA, Rostami A, Ghorbani-Choghamarani A
(2007) Catal Commun 8:543
17. Wang L, Woods KW, Li Q, Barr KJ, McCroskey RW, Hannick
SM, Gherke L, Credo RB, Hui Y-H, Marsh K, Warren R, Lee JY,
Zielinsky-Mozng N, Frost D, Rosenberg SH, Sham HL (2002) J
Med Chem 45:1697
18. Lombandine JG, Wiseman EH (1974) J Med Chem 17:1182
19. Wasserschied P, Keim W (2000) Angew Chem Int Ed 39:3772
20. Chowdhurg S, Mohan RS, Scott JL (2007) Tetrahedron 63:2363
21. Shaabani A, Rahmati A (2006) J Mol Catal A: Chem 249:246
22. Sharma SD, Hazarika P, Konwar D (2008) Tetrahedron Lett
49:2216
35. Zolfigol MA, Khazaei A, Ghorbani-Choghamarani A, Rostami A,
Hajjami M (2006) Catal Commun 7:399
36. Shen M-G, Cai C, Yi W-B (2008) J Flurine Chem 129:541
37. Joshi RS, Mandhane PG, Shaikh MU, Kale RP, Gill CH (2010)
Chin Chem Lett 21:429
38. White DM, Sonnenberg J (1964) J Org Chem 29:192
39. Safari J, Khalili SD, Banitaba SH (2011) Synth Commun 41:2359
40. Goswami S, Chakrabarty R (2011) Eur J Chem 2:410
123