p-TSA catalyzed synthesis of 2,4,5-triarylimidazoles from ammonium heptamolybdate tetrahydrate in TBAI

Article abstract of DOI:10.1002/jccs.200700121

A one-pot synthesis of 2,4,5-trisubstituted imidazoles from 1,2-diketone or α-hydroxy ketone, aldehyde and ammonium heptamolybdate tetrahydrate in an inexpensive and readily available ionic liquid, tetrabutylammonium iodide (TBAI) in molten state using catalytic amounts of p-TSA has been described.

Full text of DOI:10.1002/jccs.200700121

Journal of the Chinese Chemical Society, 2007, 54, 829-833
829
Communication
p-TSA Catalyzed Synthesis of 2,4,5-Triarylimidazoles from Ammonium
Heptamolybdate Tetrahydrate in TBAI
Mohammad Mehdi Khodaei,* Kiumars Bahrami* and Iman Kavianinia
Department of Chemistry, Razi University, Kermanshah 67149, Iran
A one-pot synthesis of 2,4,5-trisubstituted imidazoles from 1,2-diketone or a-hydroxy ketone, al-
dehyde and ammonium heptamolybdate tetrahydrate in an inexpensive and readily available ionic liq-
uid, tetrabutylammonium iodide (TBAI) in molten state using catalytic amounts of p-TSA has been de-
scribed.
Keywords: Trisubstiuted imidazoles; 1,2-Diketone; a-Hydroxy ketone; Ammonium
heptamolybdate; p-TSA; Ionic liquid.
INTRODUCTION
Heterocyclic compounds with imidazole ring sys-
°C), high cost of most conventional room temperature ionic
liquids,18 use of toxic organic solvent, and requirement of
an excess of ammonium acetate.
tems have many pharmaceutical activities and play impor-
tant roles in biochemical processes.1 Imidazole derivatives
have antiviral,2 antifungal,3 antihelmitic,4 pesticidal or her-
bicidal properties.
Recent advances in green chemistry and organome-
tallic chemistry have extended the boundary of imidazoles
to the synthesis and application of a large class of imida-
zoles as ionic liquids and imidazole related N-heterocyclic
carbenes (NHC).19,20 Ionic liquids are emerging as effec-
tive solvents for ‘green’ processes.21 These solvents are
non-flammable, non-volatile, easy to handle and possess
high thermal stability.22 However, the high cost of most con-
ventional room temperature ionic liquids and apprehension
about their toxicity23 have led us to explore the use of more
benign salts in the molten state as practical alternatives.
Highly substituted imidazoles could potentially have
novel therapeutic activities5 and thus have rekindled an in-
creased interest in obtaining tri- and tetra-substituted imi-
dazoles via absolute region controlled processes.6 Triaryl
imidazoles are used in photography7 as photosensitive
compounds. In addition, they are of interest due to their
herbicidal,8 analgesic,9 fungicidal,10 antiinflammatory11
and antithrombotic activities.12 Despite their importance
from pharmacological, industrial, and synthetic points of
view, comparatively few methods for the preparation of
trisubstituted imidazoles have been reported. These in-
clude the condensation of 1,2-diketone, aldehyde and am-
monium acetate in the presence of H3PO4,13 H2SO4,14
HOAc,15 and silica sulfuric acid.16 Recently, one-pot con-
densations of an aldehyde and ammonium acetate with
a-hydroxy ketone, a-keto-oxime or 1,2-diketone have
been performed using solid supports under microwave irra-
diation.17 Despite their potential utility, these methods have
a number of drawbacks including poor yields, utilization of
excessive glacial acetic acid, high temperature (180-200
RESULTS AND DISCUSSION
Recently, we used ionic liquids in a number of useful
synthetic transformations.24 In this report, a simple and
green method for the synthesis of 2,4,5-trisubstituted imi-
dazoles in the presence of a catalytic amount of p-toluene-
sulfonic acid (p-TSA) in ionic liquid has been described
(Scheme I).
The condensation of 1,2-diketone or a-hydroxy ke-
tone, aldehyde and ammonium acetate in the presence of a
strong protic acid, is one of the most frequently used path-
* Corresponding author. E-mail: mmkhoda@razi.ac.ir; k2005bahrami@yahoo.com

830 J. Chin. Chem. Soc., Vol. 54, No. 4, 2007
Khodaei et al.
Scheme I
ways to 2,4,5-trisubstituted imidazoles. Unfortunately, this
method involves the utilization of excessive ammonium
acetate such as eight fold17a or ten fold.9b In addition, in
most of the methods reported for the synthesis of trisubsti-
tuted imidazoles, the use of microwave irradiation condi-
tions is necessary (Table 1).
Table 1. Comparison of different methods for the synthesis of
imidazole derivatives
Entry
Conditions
Yield (%)
Time
1
2
3
4
5
6
MW/180 ºC9b
80-99
86-92
5 min
4-30 min
8 min
4 h
MW17a
MW/Silica gel30a
Excess of H2SO4/150-200 ºC30b
AcOH30c
58-92
40-90
Thus we decided to use another reagent instead of
ammonium acetate and apply ammonium heptamolybdate
tetrahydrate for the preparation of 2,4,5-trisubstituted imi-
dazoles. It was found that two equivalents of ammonium
heptamolybdate tetrahydrate were enough to perform the
reaction.
Low yield
75-95
-
p-TSA/TBAI
1-4 h
and easily accessible p-TSA and TBAI makes this method-
ology as a useful procedure for preparation of biologically
active trisubstituted imidazoles.
To explore the scope and limitations of this reaction,
we studied the reactions of benzil or benzoin with benzal-
dehydes bearing either electron-releasing or electron-with-
drawing substituents in the ortho or para positions. The re-
actions proceeded very efficiently and the results are sum-
marized in Table 2. However, it was observed that aromatic
aldehydes carrying strong electron-withdrawing groups
like 4-nitrobenzaldehyde and 3-nitrobenzaldehyde afforded
no corresponding products and the starting materials re-
mained intact.
EXPERIMENTAL SECTION
Products are known compounds and were character-
ized by comparison of their spectral data (1H NMR, IR) and
melting points with those reported in the literature. Moni-
toring of the reactions was accomplished by TLC on pre-
coated silica gel 60 F254 sheets. All yields refer to isolated
products.
These reactions in molten tetrabutylammonium io-
dide are in general, fast and clean. No reaction was ob-
served using solid tetrabutylammonium iodide at room
temperature. Also, the reaction in the absence of tetrabutyl-
ammonium iodide at 140-145 °C leads to a mixture of un-
identified products. Thus, the presence of molten tetrabutyl-
ammonium iodide is essential for an efficient and clean re-
action. In addition, the reaction in the absence of p-TSA
proceeded very slowly.
General experimental procedure
A mixture of benzil or benzoin (0.5 mmol), aldehyde
(0.5 mmol), ammonium heptamolybdate tetrahydrate (1
mmol), tetrabutylammonium iodide (1 g), and p-TSA (0.038
g) were heated at 145 °C with good stirring for the appro-
priate time as indicated in Table 2. The progress of the reac-
tion was monitored by TLC. After completion of the reac-
tion, hot ethanol (5 mL) was added and the mixture was
then filtered. The filtrate was condensed under reduced
pressure and it was diluted with water (25 mL). The sepa-
rated out solid product was filtered, washed with water and
dried. For further purification this product was recrystal-
lized from a 9:1 acetone-water solution.
In conclusion, this paper describes a convenient and
efficient process for the synthesis of trisubstituted imida-
zoles through the three-components coupling of benzil or
benzoin, aldehydes, and ammonium heptamolybdate tetra-
hydrate in ionic liquid in the presence of a catalytic amount
of p-toluenesulfonic acid. Moreover, the use of inexpensive

p-TSA Catalyzed Synthesis of Triarylimidazoles
J. Chin. Chem. Soc., Vol. 54, No. 4, 2007 831
Table 2. One-pot synthesis of trisubstituted imidazoles in TBAI in the presence of p-TSA
Mp/ºC
Entry
1
Substrates
Productsa
Time (h) Yieldb (%)
(Found)
O
Ph
Ph
Ph
N
1
1
88
95
93
88
274-27525
233-23526
230-23327
256-25727
CHO
N
H
O
Ph
Ph
O
Ph
N
Me
OMe
Me
2
3
4
CHO
N
H
Ph
O
Ph
Ph
O
Ph
N
MeO
1
CHO
N
H
Ph
Ph
Ph
O
Ph
Ph
O
N
N(Me)2
(Me)2N
1.5
CHO
N
H
O
Ph
Ph
O
Ph
Ph
N
CHO
OH
5
6
7
2.5
2
80
80
82
200-20320
261-26327
260-26228
N
H
O
Ph
Ph
HO
O
Ph
N
Cl
Cl
F
CHO
CHO
N
H
Ph
O
Ph
Ph
O
Ph
Ph
N
F
2
N
H
O
Ph
Ph
O
Ph
N
CHO
CHO
8
3.5
75
183-18420
N
H
Ph
O
Ph
Cl
Cl
O
Ph
Ph
Ph
N
9
1.5
1.5
2
85
90
88
85
274-275 25
233-23526
230-23327
256-25727
N
H
OH
O
Ph
Ph
Ph
N
Me
OMe
Me
MeO
10
11
12
CHO
N
H
Ph
OH
O
Ph
Ph
Ph
N
CHO
N
H
Ph
OH
O
Ph
Ph
Ph
N
N(Me)2
(Me)2N
2
CHO
N
H
Ph
OH
O
Ph
Ph
Ph
N
CHO
OH
200-20320
261-26327
13
14
3
3
80
80
N
H
Ph
HO
OH
O
Ph
Ph
Ph
N
Cl
Cl
CHO
N
H
Ph
OH
Ph

832 J. Chin. Chem. Soc., Vol. 54, No. 4, 2007
Khodaei et al.
O
Ph
Ph
N
260-26228
183-18420
F
F
15
16
3
4
80
75
CHO
CHO
N
H
Ph
OH
O
Ph
Ph
Ph
N
N
H
Ph
OH
O
Cl
Ph
Ph
Cl
Ph
N
233-23529
233-23529
17
18
2
2
87
90
CHO
CHO
O
O
N
H
Ph
O
O
OH
O
Ph
Ph
Ph
N
N
H
Ph
O
Ph
a The products were characterized by comparison of their spectroscopic and physical data with authentic samples synthesized
by reported procedures.
b Yields refer to pure isolated products.
56, 285. (b) Wolkenberg, S. E.; Wisnosk, D. D.; Leister, W.
H.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6,
1453.
ACKNOWLEDGEMENTS
We are grateful to the Research Council of Razi Uni-
versity for partly financial support of this work.
10. Pozherskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R.
Heterocycles in Life, Society; Wiley: New York, 1997; p 179.
11. Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17,
1182.
Received September 6, 2006.
12. Phillips, A. R.; White, H. L.; Rosen, S. Eur. Pat. Appl. EP
58,890; Chem. Abstr. 1982, 98, 53894z.
13. Liu, J.; Chem, J.; Zhao, J.; Zhao, Y.; Li, L.; Zhang, H. Syn-
thesis 2003, 2661.
REFERENCES
14. Weinmann, H.; Harre, M.; Koeing, K.; Merten, E.; Tilestam,
U. Tetrahedron Lett. 2002, 43, 593.
1. (a) Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974,
17, 1182. (b) Sundberg, R. J.; Martin, R. B. Chem. Rev. 1974,
74, 471.
15. Sarshar, S.; Siev, D.; Mjalli, A. M. M. Tetrahedron Lett.
1996, 37, 835.
2. Bartlett, M.; Shaw, M.; Smith, J. W. J. Med. Chem. Chim.
Ther. 1992, 36, 779.
16. Shaabani, A.; Rahmati, A. J. Mol. Catal. A: Chem. 2006,
249, 246.
3. Gbadamassi, M.; Barascut, J.; Imbach, J. L.; Gayral, P. Eur.
J. Med. Chem. 1988, 23, 225.
17. (a) Zhao, N.; Wang, Y.-L.; Wang, J.-Y. J. Chin. Chem. Soc.
2005, 52, 535. (b) Xu, Y.; Wan, L. F.; Salehi, H.; Deng, W.;
Guo, Q. X. Heterocycles 2004, 63, 1613. (c) Sparks, R. B.;
Combs, A. P. Org. Lett. 2004, 6, 2473. (d) Usyatinsky, A. Y.;
Khmelnitsky, Y. L. Tetrahedron Lett. 2000, 41, 5031.
18. Siddiqui, S. A.; Narkhede, U. C.; Palimkar, S. S.; Daniel, T.;
Lahoti, R. J.; Srinivasan, K. V. Tetrahedron 2005, 61, 3539.
19. (a) Welton, T. Chem. Rev. 1999, 99, 2071. (b) Wasserscheid,
P.; Keim, W. Angew. Chem. Int. Ed. Eng. 2000, 39, 3772.
20. (a) Hermann, W. A.; Kocher, C. Angew. Chem. Int. Ed. Eng.
1997, 36, 2162. (b) Zhang, C.; Huang, J.; Trudell, M. L.;
Nolan, S. P. J. Org. Chem. 1999, 64, 3804. (c) Bourissou, D.;
Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000,
100, 39.
4. Hazelton, J.; Iddon, B.; Redhouse, A. D.; Suschitzky, H.
Tetrahedron 1995, 51, 5597.
5. Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. T.;
Kumar, S.; Green, D.; McKulty, D.; Blumenthal, M.; Heys, J.
R.; Landvatter, S. W.; Strikler, J. E.; McLaughlin, M. M.;
Siemen, I. R.; Fisher, S. M.; Livi, G. P.; White, J. R.; Adams,
J. L.; Young, P. R. Nature 1994, 372, 739.
6. Li, H.-S.; Rampersaud, A. A.; Zimmerman, K. J. Chin.
Chem. Soc. 1993, 40, 273.
7. Sensui, H.; Ichikawa, J.; Sato, S. Jpn. Kokai Tokyo Koho JP
62, 94,841; Chem. Abstr. 1987, 107, 187436q.
8. Liebl, R.; Handte, R.; Mildenberger, H.; Bauer, K.; Bieringer,
H. Ger. Offen DE 3,604,042; Chem. Abstr. 1987, 108, 6018g.
9. (a) Ucucu, U.; Karaburun, N. G.; Isikdag, I. Farmaco. 2001,
21. (a) Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetrahedron
Lett. 2002, 43, 1127. (b) Namboodiri, V. V.; Varma, R. S.

p-TSA Catalyzed Synthesis of Triarylimidazoles
J. Chin. Chem. Soc., Vol. 54, No. 4, 2007 833
Chem. Commun. 2002, 342. (c) Sheldon, R. Chem. Commun.
2001, 2399. (d) Wasserscheid, P.; Keim, W. Angew. Chem.,
Int. Ed. 2000, 39, 3773.
Khosropour, A. R.; Ghaderi, S. J. Iranian Chem. Soc. 2006,
3, 69.
25. (a) Hellmut, B.; Rudolf, G.; Dieter, H. Chem. Ber, 1959, 92,
338. (b) Xu, Y.; Wan, L.-F.; Salehi, H.; Deng, W.; Guo, Q.-X.
Heterocycles 2004, 63, 1613.
22. (a) Ganchegui, B.; Bouquillon, S.; Henin, F.; Muzart, J. Tet-
rahedron Lett. 2002, 43, 6641. (b) Ranu, B. C.; Das, S.;
Samanta, S. J. Chem. Soc., Perkin Trans.1 2002, 1520. (c)
Selvakumar, K.; Zapt, A.; Beller, M. Org. Lett. 2002, 4,
3031. (d) Amantini, C.; Fringuelli, F.; Pizzo, F.; Vaccaro, L.
J. Org. Chem. 2001, 66, 6734. (e) Smietana, M.; Mioskowski,
C. Org. Lett. 2001, 3, 1037.
26. Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17,
1182.
27. Whiten, D. M.; Sonnenberg, B. J. Org. Chem. 1964, 29,
1926.
28. Philbrook, G. E.; Maxwell, M. A.; Taylor, R. E.; Totter, J. R.
Photochem. Photobiol. 1965, 4, 1175.
23. Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Venkat Narsaiah,
A. Tetrahedron Lett. 2003, 44, 1047.
29. Kidwai, M.; Saxena, Sh.; Rastogi, Sh. Bull. Korean Chem.
Soc. 2005, 26, 2051.
24. (a) Khodaei, M. M.; Khosropour, A. R.; Kookhazadeh, M.
Synlett 2004, 1980. (b) Khodaei, M. M.; Khosropour, A. R.;
Ghozati, K. Tetrahedron Lett. 2004, 45, 3525. (c) Khosropour,
A. R.; Khodaei, M. M.; Kookhazadeh, M. Tetrahedron Lett.
2004, 45, 1725. (d) Khosropour, A. R.; Khodaei, M. M.;
Bigzadeh, M.; Jokar, M. Hetrocycles 2005, 65, 767. (e)
Khosropour, A. R.; Khodaei, M. M.; Ghozati, K. Z.
Naturforsch., B 2005, 60b, 572. (f) Khodaei, M. M.;
30. (a) Balalaie, S.; Hashemi, M. M.; Akhbari, M. Tetrahedron
Lett. 2003, 44, 1709. (b) Grimmett, M. R. In Comperhensive
Hetercyclic Chemistry; Kattritzky, A. R.; Rees, C. W., Eds.;
Pergamon: New York, 1984; Vol. 5, p 457. (c) Wasserman, H.
H.; Long, Y. O.; Zhang, R.; Parr, J. Tetrahedron Lett. 2002,
43, 3351.