Available online at www.sciencedirect.

com

Chinese Chemical Letters 19 (2008) 1143–1146

www.elsevier.com/locate/cclet

An expeditious and one-pot synthesis of unsymmetrical

2,5-disubstituted-1,3,4-oxadiazoles under microwave
irradiation and solvent-free conditions
Nasser Montazeri a,*, Kurosh Rad-Moghadam b
a
Chemistry Department, Azad University of Tonekabon, Tonekabon 46841-61167, Iran
b
Chemistry Department, University of Guilan, Rasht, P.O. Box 41335-1914, Iran
Received 28 January 2008

Abstract
A one-pot synthesis of some unsymmetrical 2,5-disubstituted-1,3,4-oxadiazoles via cyclocondensation of benzoylhydrazines
with orthoesters under solvent-free and microwave conditions are described here. The reaction is efficiently catalyzed by silica-
supported sulfuric acid as it provided the title compounds in high yields and relatively short times. The catalyst is reusable and can
be applied several times without considerable decrease in the yields and rates of the reactions.
# 2008 Nasser Montazeri. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: 2,5-Disubstituted-1,3,4-oxadiazoles; Silica-supported sulfuric acid; Solvent-free; Microwave; Orthoester

The 1,3,4-oxadiazole ring system has been identified as the main core of many bioactive molecules. Compounds
containing these aromatic five-membered heterocycles have been shown to exert anti-inflammatory [1], antimicrobial
[2], anti-convulsant [3], and hypoglycaemic [4] activities. In addition, 2,5-disubstituted-1,3,4-oxadiazoles are
proposed to have potential agrochemical use [5] due to their wide spectrum of insecticidal [6] and acaricidal [7]
properties attained by interfering with insect’s chitin biosynthesis [8]. This class of materials also has gained the worth
of modern applications such as scintillators, fluorescence and photographic materials [9]. They are of interest as
emitting layers in electroluminescent devices [10] and as structural units in polymeric membranes designed for gas
separation applications [11]. Because of these interesting features several routes to the synthesis of 1,3,4-oxadiazoles
have been developed. A majority of the 2,5-disubstituted-1,3,4-oxadiazoles have been synthesized from
cyclodehydration of diacylhydrazines. This method of synthesis usually involves rigorous conditions or use of
harsh reagents, e.g. POCl3 [12], SOCl2 [13], polyphosphoric acid [14], liquid sulfuric acid [15], phosphorus pentoxide
[16], triflic anhydride [17], and BF3–OEt2 [18]. Mild dehydrating agents like Burgess reagent [19] and carbodiimides
are also used in this manner [20]. Another more popular route to the synthesis of 1,3,4-oxadiazoles is based on the
preparation of acylhydrazones from unprotected acylhydrazines and aldehydes, followed by oxidation with a variety
of oxidizing agents [21]. By a similar approach but in a non-oxidative media, trichloroacetylhydrazones gave 1,3,4-

* Corresponding author.
E-mail address: montazer50@yahoo.com (N. Montazeri).

1001-8417/$ – see front matter # 2008 Nasser Montazeri. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2008.06.050
1144 N. Montazeri, K. Rad-Moghadam / Chinese Chemical Letters 19 (2008) 1143–1146

Table 1
Yields and conditions of 1,3,4-oxadiazoles formation
Product R X Y Equivalents of Microwave irradiation cycles Yielda (%) mp (8C) Lit. mp (8C)
orthoester (power and time)
P1 (W) t (min) t (min) P2 (W)
4a H Cl H 4 180 2 4 480 93 133–134 134–135 [29]
4b Me Cl H 3 180 2 5 480 87 106–107 107 [30]
4c Et Cl H 3 180 3 5 480 90 94–95 93–94 [29]
4d Ph H H 2.5 180 4 6 480 88 138–139 138–139 [31]
4e Ph Cl H 2.5 180 4 6 480 94 161–162 157–158 [32]
4f Ph H NO2 2.5 180 5 6 480 91 151–152 147 [33]
a
Yields of isolated products.

oxadiazoles through a formal oxidation of aldehyde-derived moiety of hydrazones [22]. To exclude the oxidation step,
carboxylic acids have directly been used instead of aldehydes in the synthesis of 1,3,4-oxadiazoles via reaction with
hydrazines [23]. Orthoesters are readily available carboxylic acid derivatives which react with acylhydrazines in
milder and acid catalyzed conditions to afford 2,5-disubstituted-1,3,4-oxadiazoles [24]. However, many of these
methods suffer from drawbacks such as long reaction times [25], unsatisfactory yields, special care in handling and
storing the reagents, undesired side products in reaction with harsh reagents [26], using heavy metal oxidants [21],
cumbersome product isolation procedure and environmental pollution. Therefore, a need still exists for further
development of versatile and milder reaction conditions, using green and reusable catalysts. Use of catalysts in one-pot
synthesis of heterocycles has continually been the interest of organic chemists who planned to develop concise and
direct synthetic methods [27]. Recently, we reported our research findings on the application of silica-supported
sulfuric acid (H2SO4/SiO2) as a catalyst in the synthesis of quinazolin-4(3H)-ones [28]. In continuation, we wish to
introduce here a combination of H2SO4/SiO2 and microwave irradiation as an efficient condition in the synthesis of
2,5-disubstituted-1,3,4-oxadiazoles from a solvent-less reaction of benzoylhydrazines and orthoesters.
Thus, a mixture of benzoylhydrazine 1 and 2.5–4 equiv. of orthoester 2 was subjected to reaction. This reaction
effected with the aid of H2SO4/SiO2 and submission to microwave irradiation to provide fairly high yields of 2,5-
disubstituted-1,3,4-oxadiazoles 4a–f in a few minutes (see Table 1) (Scheme 1).
In the same time but absence of catalyst, or by mixing the catalyst with reactants without exposure to microwave
irradiation no considerable reaction took place. Furthermore, without impregnation of silica gel with sulfuric acid the
reactions lengthened about 6–8 times more even under microwave irradiation to give nearly the same yields as using
SiO2–H2SO4. In situ conversion of microwaves to heat by reactants generate a nearly uniform thermal profile that in
conjunction with electric field of microwaves may rise to some rate enhancement and improvement of yields [34]. In
these situations, unlike the conventional heating methods the role of solvents as heat dispersants is no longer needed.
Therefore, microwave condition is best suited to the so-called solvent-free reactions. These reactions are eco-friendly
and in view of green-chemistry’s desire for avoiding the solvent hazards, are in demand. The early reactions of

EtO R R
O O OH
Y NH2 Y N Y N
N SiO2 / H2SO4 N + H+ N OEt
H + R-C(OEt)3 +
H H
MW
X X X
1 2 3
X = H or Cl
Y = H or NO 2
R R
H
+
O O
N N
Y -H + Y
N N

4a-f
X X

Scheme 1. .
 N. Montazeri, K. Rad-Moghadam / Chinese Chemical Letters 19 (2008) 1143–1146 1145

acylhydrazines with orthoesters were carried out with much excess of orthoesters in two steps. The intermediate imidic
esters 3 produced in the refluxing condition of first step were separated and subsequently cyclized on heating to the
1,3,4-oxadiazoles [24]. Though, in the present work an excess of orthoester is necessary to diminish the intermolecular
side-reactions, the conventional heating method even needs additional orthoesters both to act in place of solvent and to
improve the yields. In contrast to the liquid H2SO4, which is difficult to recovery and takes some effort in work-up, the
silica-supported H2SO4 can be easily separated and recycled without considerable loss of activity for three times. To
investigate the reusability of SiO2–H2SO4 the condensation of 4-chlorobenzoylhydrazine with triethyl
orthopropionate was chosen as the model reaction. For this purpose after completion of reaction the catalyst was
washed with acetone and then subjected to the next run with the same substrate and the same reaction time. The results
of the first and subsequent experiments were almost consistent in yields after three runs (90%, 88% and 84%).
Although, the reactions took place quite fast in the microwave conditions still a reasonable trend is detectable from
varied rates of different substrates (Table 1). Part of the rate discrepancies can be ascribed to the different reactivity of
orthoesters. As is evident in Table 1 reactions with more hindered orthoesters take more time to be completed. In
addition, the cyclization of the intermediate imidic esters 3 reasonably depends on nucleophilic character of the
carbonyl group, which in turn is affected by electronic nature of the attached phenyl group. According to Table 1, the
presence of a chlorine substituent at para position to the carbonyl group has no net effect on the rate of reaction with
trimethyl orthobenzoate but a nitro substituent even at meta position due to its electron-withdrawing nature slows
down the reaction.
In conclusion we have developed a one-pot synthesis of 2,5-disubstituted-1,3,4-oxadiazoles under microwave
irradiation using sulfuric acid adsorbed on silica gel as an eco-friendly, non-toxic, reusable, and efficient catalyst.
Fairly high yields, relatively short reaction times, simple operation and easy work-up procedure are some advantages
of this protocol.

1. Experimental

Melting points are uncorrected. All products are known compounds and identified by comparison with authentic
samples. Microwave irradiations were carried out in a domestic 1000 W oven at 2450 MHz. Chemicals were obtained
from Merck or Fluka companies and were used without further purification.
General procedure: A mixture of benzhydrazide 1 (0.004 mole), orthoester (0.010–0.016 mole according to
Table 1) and 0.2 g of finely ground silica-supported sulfuric acid was placed in a 20-mL glass tube. The tube was
irradiated in the microwave oven for appropriate time and power (according to Table 1). After completion of the
reaction (monitored by TLC using ethyl acetate:hexane, 1:1), the residue was washed with ethyl acetate or acetone.
The solvent of combined extraction solution was evaporated and the crude product thus obtained was recrystallized
from ethanol 95.5%. The catalyst could be washed with acetone and reused.

References

[1] (a) M. Amir, S. Shahani, Indian J. Heterocycl. Chem. 8 (1998) 107;

(b) F.A. Omar, N.M. Mahfouz, M.A. Rahman, Eur. J. Med. Chem. 31 (1996) 819;
(c) Z.K. El Samii, Chin. Pharm. J. 43 (1991) 245;
(d) M. Kidwai, N. Negi, S.R. Chowdhury, Acta Pharm. 45 (1995) 511;
(e) M. Amir, R. Agarwal, Indian J. Heterocycl. Chem. (1998) 225.
[2] (a) F.A. Ashour, S.A. Al Mazoroa, J. Pharm. Sci. 4 (1990) 29;
(b) I.A. Shehata, M.N. Nasr, H.I. El Subbagh, M.M. Gineinah, S.M. Kheira, Sci. Pharm. 64 (1996) 133.
[3] (a) O.M. Nassar, Indian J. Heterocycl. Chem. 7 (1997) 105;
(b) P. Tsitsa, A.P. Valiraki, T.S. Papastaikoudi, Z.P. Daifoiti, A. Vamvakidis, Ann. Pharm. Fr. 47 (1989) 296.
[4] N.A. Mohamed, Polym. Degrad. 44 (1994) 33.
[5] H.L. Plant, R.R. Regis, R.C. Moore, Eur. Pat. Appl. EP 156,638 A2 (1985).
[6] I.R. Matthews, D.P. Bacon, PCT Int. Appl. WO 9505368 A1 (1995).
[7] U. Kraatz, B. Gallenkamp, A. Marhold, P. Wolfrum, WO 2002006256 A1 (2002).
[8] J.P. Arrington, L.L. Wade, US Patent 42,151,29 (1980).
[9] W. Wiedemann, Chem. Z. 106 (1982) 313.
[10] M. Meier, E. Buchwald, S. Karg, P. Pösch, P. Strohriegl, W. Rieß, Synth. Met. 76 (1996) 95.
[11] D. Gomes, C.P. Borges, J.C. Pinto, Polymer 42 (2001) 851.
[12] J. Dost, M. Heschel, J. Stein, J. Prakt. Chem. 327 (1985) 109.
1146 N. Montazeri, K. Rad-Moghadam / Chinese Chemical Letters 19 (2008) 1143–1146

[13] (a) M. Al Talib, H. Tashtoush, N. Odeh, Synth. Commun. 20 (1990) 1811;

(b) N.V. Kerr, D.G. Ott, F.N. Hayes, J. Am. Chem. Soc. 82 (1960) 186.
[14] W.G. Tully, C.R. Gardner, R.J. Gillespie, W. Westwood, J. Med. Chem. 34 (1991) 2060.
[15] F.W. Short, L.M. Long, J. Heterocycl. Chem. 6 (1969) 707.
[16] H.J. Carlsen, K.B. Jorgensen, J. Heterocycl. Chem. 31 (1994) 805.
[17] S. Liras, M.P. Allen, B.E. Segelstein, Synth. Commun. 30 (2000) 437.
[18] V.K. Tandon, R.B. Chhor, Synth. Commun. 31 (2001) 1727.
[19] C.T. Brain, J.M. Paul, Y. Loong, P.J. Oakley, Tetrahedron Lett. 40 (1999) 3275.
[20] J.P. Kilburn, J. Lau, R.C.F. Jones, Tetrahedron Lett. 42 (2001) 2583.
[21] (a) P.S.N. Reddy, P.R. Reddy, Indian J. Chem. 26B (1987) 890;
(b) T. Chiba, M. Okimoto, J. Org. Chem. 57 (1992) 1375;
(c) R. Yang, L. Dai, J. Org. Chem. 58 (1993) 3381;
(d) S. Rostamizadeh, G. Housaini, Tetrahedron Lett. 45 (2004) 8753;
(e) K.S. Balachandran, M.V. George, Tetrahedron 29 (1973) 2119.
[22] L. El Kaim, I. Le Menestrel, R. Morgentin, Tetrahedron Lett. 39 (1998) 6885.
[23] F. Bentiss, M. Lagrenee, J. Heterocycl. Chem. 36 (1999) 1029.
[24] (a) C. Ainsworth, J. Am. Chem. Soc. 77 (1955) 1148;
(b) R.W. Leiby, J. Heterocycl. Chem. 21 (19841825);
(c) A. Shafiee, E. Naimi, P. Mansobi, A. Foroumadi, M. Shekari, J. Heterocycl. Chem. 32 (1995) 1235.
[25] B. Rigo, P. Cauliez, D. Fasseurand, D. Couturier, Synth. Commun. 18 (1988) 1247.
[26] A.E. Siegrist, E. Moergeli, US Patent 2,765,304 (1956).
[27] (a) P. Biginelli, Gazz. Chim. Ital. (1893) 360;
(b) Z. Zhang, Y. Ma, Y. Zhao, Synlett (2008) 1091.
[28] N. Montazeri, K. Rad-Moghadam, Phosphorus Sulfur Silicon 179 (2004) 2533.
[29] A. Hetzheim, K. Mockel, Adv. Heterocycl. Chem. 7 (1966) 183.
[30] W.A.F. Gladstone, J.B. Aylward, R.O.C. Norman, J. Chem. Soc. C (1969) 2587.
[31] F.M. Hayes, B.S. Rogers, D.G. Ott, J. Am. Chem. Soc. 77 (1955) 1850.
[32] C.J. Goddard, J. Heterocycl. Chem. 28 (1991) 17.
[33] A.P. Grekov, R.S. Azen, Zh. Obshch. Khim. 31 (1961) 1919.
[34] (a) A. Loupy (Ed.), Microwaves in Organic Synthesis, 2nd ed., Wiley–VCH, Weinheim, 2006;
(b) A. de la Hoz, A. Diaz-Ortiz, A. Moreno, Chem. Soc. Rev. 34 (2005) 164.