1
710
S. Balalaie et al. / Tetrahedron Letters 44 (2003) 1709–1711
microwave oven. Silica gel is used as a solid support in
all of the experiments. Reaction of benzonitrile, benzil
and benzylamine on the surface of silica gel under
for 8 min (optimized time) at 850 W. The progress of
reaction was monitored by TLC using CH Cl –
2
2
petroleum ether as eluent. The mixture was extracted
with chloroform, and the solvent was removed by
rotary evaporation. Further purification by column
chromatography and recrystallization gave the desired
products.
1
microwave irradiation produces 4a. IR and H NMR
spectra of the product clearly indicated the formation
of tetrasubstituted imidazole 4a. The same reactions
were carried out using benzil, benzonitrile derivatives
and primary amines under the same conditions. The
results are summarized in Table 1.
References
The structures of compounds 4a–h were deduced from
1
their elemental analyses, H NMR and IR spectral data
1
2
. Grimmett, M. R. In Comprehensive Heterocyclic Chem-
istry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon
Press: London, 1984; Vol. 5, pp. 374–498.
and melting points. The three-component condensation
of benzil, benzonitrile and benzylamine was also per-
formed in the absence of silica gel under neat condi-
tions and microwave irradiation; however, the yield of
. (a) Lambardino, J. G.; Wiesman, E. H. J. Med. Chem.
1
2
974, 17, 1182; (b) Lombardino, J. G. Ger. Offen.
,155,558, 1972 (Chem. Abstr. 1972, 77, 101607y); (c)
Phillips, A. P.; White, H. L.; Rosen, S. Eur. Pat. Appl.
EP 58890, 1982 (Chem. Abstr. 1982, 98, 53894z).
4
a was low (10%). A further problem encountered with
these conditions is that the reactants and products
adhered to the reaction vessel and led to irreproducible
results. The temperature of the reaction mixture was
3
. (a) Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gal-
lagher, T. F.; Kumar, S.; Green, D.; McNulty, D.; Blu-
menthal, M.; Heys, J. R.; Landvatter, S. W.; Strickler, J.
E.; McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.;
Livi, J. P.; White, J. R.; Adams, J. L.; Young, P. R.
Nature 1994, 372, 739; (b) Liverton, N. J.; Butcher, J.
W.; Claiborne, C. F.; Claremon, D. A.; Libby, B. E.;
Nguyen, K. T.; Pitzenberger, S. M.; Selnick, H. G.;
Smith, G. R.; Tebben, A.; Vacca, J. P.; Varga, S. L.;
Agrawal, L.; Dancheck, K.; Forsyth, A. J.; Fletcher, D.
S.; Frantz, B.; Hanlon, W. A.; Harper, C. F.; Hofsess,
S. J.; Kostura, M.; Lin, J.; Luell, S.; O’Neill, E. A.;
Orevillo, C. J.; Pang, M.; Parsons, J.; Rolando, A.;
Sahly, Y.; Visco, D. M.; O’Keefe, S. J. J. Med. Chem.
999, 42, 2180–2190.
4. Lantos, I.; Zhang, W. Y.; Shui, X.; Eggleston, D. S. J.
Org. Chem. 1993, 58, 7092–7095.
5. (a) Zhang, C.; Moran, E. J.; Woiwode, T. F.; Short, K.
M.; Mjalli, A. M. M. Tetrahedron Lett. 1996, 37, 751–
754; (b) Sarshar, S.; Siev, D.; Mjalli, A. M. M. Tetra-
hedron Lett. 1996, 37, 835–838.
90°C at the end of irradiation under solvent-free condi-
tions. Carrying out the condensation in refluxing tolu-
ene for 29 h resulted in 4a with an 82% yield. Although
we have not experimentally established the mechanism
of formation of products, it seems that the existence of
silica gel as acidic support under microwave irradiation
can accelerate this new cyclocondensation reaction by
increasing the reactivity of benzonitrile derivatives and
benzil, and also by supporting the formation of polar
1
4
intermediates.
In conclusion, the one-pot nature of the present proce-
dure makes it an acceptable alternative to multi-step
approaches. It also simplifies the laborious procedures
and offers considerable advantages, such as: elimination
of solvents, the use of substances without any modifica-
tion or activation, high yields, short reaction times,
employment of reusable solid catalysts and environ-
mentally friendly character over the existing
methodologies.
1
General procedure for the synthesis of tetrasubstituted
imidazoles (4a–h):
6. Claiborne, C. F.; Liverton, N. J.; Nguyen, K. T. Tetra-
hedron Lett. 1998, 39, 8939–8942.
1
5
7
. Lee, H. B.; Balasubramanian, S. Org. Lett. 2000, 2,
23–326.
. (a) Bose, A. K.; Manhas, M. S.; Ganguly, S. N.;
Benzil (421 mg, 2 mmol), benzonitrile derivatives (2–3
mmol), primary amine (3–5 mmol) and 2 g of silica gel
were mixed thoroughly in a mortar. The reaction mix-
ture was then irradiated in a domestic microwave oven
3
8
Sharma, A. H.; Banik, B. K. Synthesis 2002, 1578–1591;
(
b) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mathe, D. Synthesis 1998, 1213; (c)
Varma, R. S. Green Chem. 1999, 1, 43; (d) Varma, R. S.
Clean Prod. Proc. 1999, 1, 132.
Table 1. Solvent-free synthesis of tetrasubstituted imida-
zoles under microwave irradiation
Yield (%)a
9. (a) Balalaie, S.; Hashtroudi, M. S.; Sharifi, A. J. Chem.
Res. 1999, 392–393; (b) Balalaie, S.; Nemati, N. Hetero-
cyclic Commun. 2001, 7, 67–72; (c) Balalaie, S.; Sharifi,
A.; Ahangarian, B.; Kowsari, E. Heterocyclic Commun.
2001, 7, 337–342; (d) Balalaie, S.; Kowsari, E. Monatsh.
Chem. 2001, 132, 1551–1555; (e) Balalaie, S.; Kowsari,
E.; Hashtroudi, M. S. Monatsh. Chem., in press.
0. Balalaie, S.; Arabanian, A.; Hashtroudi, M. S. Monatsh.
Chem. 2000, 131, 945–948 and references cited therein.
1. Balalaie, S.; Arabanian, A. Green Chem. 2000, 2, 274–
276 and references cited therein.
Ar
R
a
b
c
d
e
f
Ph
Ph
PhCH2
PhCH(CH3)
87
92
78
87
90
90
65
58
4-CH C H
4-CH C H
4-CH C H
4-CH C H
3-BrC H4
3-NH C H
4
CH3
3
6
4
4
4
4
C H
5
3
6
2
iso-C H
3
6
4
9
PhCH2
PhCH2
PhCH2
3
6
1
1
g
h
6
2
6
a
In all experiments, the optimized time of irradiation was 8 min.