Alum (KAl(SO4)2 ? 12H2O): An efficient and inexpensive catalyst for the one-pot synthesis of 1,3,4-oxadiazoles under solvent-free conditions

Article abstract of DOI:10.1007/s00706-007-0724-0

Alum (KAl(SO₄)₂ ? 12H₂O) catalyzed the efficient synthesis of mono- and disubstituted 1,3,4-oxadiazoles by the condensation of acyl hydrazides with orthoesters under solvent-free conditions at 100°C. This methodology offers significant improvements for the synthesis of oxadiazoles with regard to the yield of products, simplicity in operation, inexpensive reagents, and green aspects by avoiding toxic catalysts and solvents.

Full text of DOI:10.1007/s00706-007-0724-0

Monatshefte fu¨r Chemie 138, 1253–1255 (2007)
DOI 10.1007/s00706-007-0724-0
Printed in The Netherlands
à
Alum (KAl(SO4)2 12H2O): An Efficient and Inexpensive Catalyst
for the One-pot Synthesis of 1,3,4-Oxadiazoles under Solvent-Free Conditions
Minoo Dabiri1;ꢀ, Peyman Salehi2, Mostafa Baghbanzadeh1, and Mahboobeh Bahramnejad1
1
Department of Chemistry, Faculty of Science, Shahid Beheshti University, Tehran, Iran
2
Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Tehran, Iran
Received May 17, 2007; accepted May 18, 2007; published online September 24, 2007
# Springer-Verlag 2007
Summary. Alum (KAl(SO4)2 ꢁ 12H2O) catalyzed the effi-
with different orthoesters in the presence of an acid
catalyst which afforded the 2,5-disubstituted 1,3,4-
cient synthesis of mono- and disubstituted 1,3,4-oxadiazoles
by the condensation of acyl hydrazides with orthoesters under
oxadiazoles [15]. Unfortunately, most of the proce-
solvent-free conditions at 100ꢂC. This methodology offers
significant improvements for the synthesis of oxadiazoles with
dures which have been described for this reaction
entail using toxic reagents or solvents, long reaction
times, or using domestic microwave ovens which
could not be adapted to an industrial scale and fur-
thermore repeatability was low in this method.
There is an increasing interest in the use of en-
vironmentally benign reagents, conditions, and partic-
ularly to solvent-free procedures. Avoiding organic
solvents during the reactions in organic synthesis
leads to a clean, efficient, and economical technolo-
gy [16].
In continuation of our interest in using solid acidic
catalysts in synthesis of heterocyclic compounds [17]
we report herein a one-step synthesis of substituted
oxadiazoles from acyl hydrazides and orthoesters
in the presence of KAl(SO4)2 ꢁ 12H2O (alum) [18] as
a solid catalyst, under solvent-free conditions. This
method appeared to be efficient and economical, with
a wide range of applications.
regard to the yield of products, simplicity in operation, inex-
pensive reagents, and green aspects by avoiding toxic catalysts
and solvents.
Keywords. Heterocycle; Oxadiazole; Solvent-free; Alum.
Introduction
Molecules containing a 1,3,4-oxadiazole core have
been shown to have a broad range of important biolog-
ical activities including antibacterial [1], antimicrobial
[2], hypotensive [3], insecticidal [4], herbicidal, and
antifungal [5] properties. Consequently, the synthesis
of this heterocycle has attracted considerable atten-
tion and a wide variety of methods have been used
for its assembly [6]. By far the most common strate-
gy involves the dehydrative cyclization of diacylhy-
drazides, usually with strongly acidic reagents such
as POCl3 [7], SOCl2 [8], P2O5 [9], H2SO4 [10], or
PPA [11]. More recently, however, several methods
have been developed using essentially neutral con-
ditions and cyclization mediators such as Tf2O [12]
and HMDS=TBAF [13], as well as solid supported
cyclization reagents [14]. Among them one simple
and efficient method is the reaction of acyl hydrazides
Results and Discussion
For optimizing the reaction conditions, reaction of
p-chlorobenzohydrazide (1; R1 ¼ Cl, R2 ¼ H) and
trimethyl orthoformate (2; R3 ¼ H, R4 ¼ Me) in the
presence of a catalytic amount of alum at different
temperatures was investigated under solvent-free
ꢀ
Corresponding author. E-mail: m-dabiri@sbu.ac.ir

1254
M. Dabiri et al.
Scheme 1
Table 1. Synthesis of 1,3,4-oxadiazoles in the presence of catalytic amounts of alum under solvent-free condition at 100ꢂC in 6 h
Product
R1
R2
R3
R4
Yield=%a
Mp=ꢂC
Ref.b
3a
3b
3c
3d
3e
3f
3g
3h
3i
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
Me
n-Pr
n-Bu
Et
Ph
Ph
H
Me
Ph
Me
H
Me
Et
Et
Me
Et
Et
Et
Me
Et
Et
Et
Me
Et
95
82
93
87
90
95
85
93
85
92
86
89
92
133–134
106–107
76–78
69–71
93–94
160–162
147–149
125–126
156–158
138–139
65–67
[15d]
[16k]
[15d]
[15d]
[15d]
[19]
[15e]
–
H
NO2
NO2
NO2
H
H
H
–
3j
3k
3l
[19]
[15e]
–
H
H
150–152
104–105
3m
H
Et
–
a
Yield of isolated product based on acyl hydrazide
The products were characterized by comparison of their spectroscopic and physical data with authentic samples synthesized by
the procedures given in the references
b
condition. It was found that the best result was ob-
tained with 40 mol% of alum at 100ꢂC. The reaction
was completed within 6 h and the expected product
(3a) was obtained in 95% yield (Scheme 1). After
screening several Lewis acids we found that alum
was the best promoter for this reaction.
Different kinds of substituted aromatic acyl hy-
drazides were subjected to the reaction with a variety
of orthoesters and the corresponding 2-mono- or 2,5-
disubstituted 1,3,4-oxadiazoles were isolated in good
to excellent yields (Table 1). It is noteworthy that
conducting similar reactions in EtOH under reflux
conditions after 2 days gave only a few percent of
the desired products.
In conclusion, we developed a simple one-step
method for the preparation of unsymmetrically sub-
stituted 1,3,4-oxadiazoles from the corresponding
commercially available acyl hydrazides and ortho-
esters. The method offers several advantages includ-
ing high yield of products, short reaction times, and
ease of work-up procedure.
Experimental
Melting points were measured on an Electrothermal 9200 ap-
paratus. IR spectra were recorded on a FT-IR 102MB BOMEM
apparatus. Mass spectra were recorded on a FINNIGAN-MAT
8430 mass spectrometer operating at an ionization poten-
1
tial of 70 eV. H and 13C NMR spectra were recorded on a
BRUKER DRX-300 AVANCE spectrometer at 300.13 and
75.47 MHz.
General Procedure for the Synthesis of 1,3,4-Oxadiazoles
To a mixture of 2 mmol acyl hydrazide and 2 cm3 orthoester
2 0.4 mmol alum were added and mixed thoroughly in a round
bottom flask and heated at 100ꢂC. After the reaction was
completed, which was indicated by TLC (eluent: n-hexane=
ethyl acetate ¼ 2=1), the mixture was allowed to cool to room
temperature and cold water was added to the mixture. The
solid product was filtered off and washed with 3ꢃ10cm3
water. Finally, the crude product was recrystallized from
EtOH to afford the pure products 3a–3m in fairly good yields.
Products 3a–3g, 3j, and 3k are known compounds and their
physical data, IR, H, and 13C NMR spectra were essentially
identical with those of authentic samples. Products 3h, 3i, 3l,
and 3m are new compounds and they were characterized by
their spectroscopic data (IR, H and 13C NMR, and MS).
1
1

Alum (KAl(SO4)2 ꢁ 12H2O)
1255
(1991) Phosphorus, Sulfur Silicon Relat Elem 57: 11; e)
Milcent R, Barbier G (1983) J Heterocycl Chem 20: 77;
f) Singh SP, Batra H, Sharma PK (1997) J Chem Res (S)
12: 468; g) Lutun S, Hasiak B, Couturier D (1999) Synth
Commun 29: 111; h) Isobe T, Ishikawa T (1999) J Org
Chem 64: 6989; i) Tandon VK, Chhor RB (1999) Synth
Commun 31: 1727; j) Natero R, Koltun DO, Ablocki JA
(2004) Synth Commun 34: 2523; k) Sharma GVM,
Begum A, Krishna PR (2004) Synth Commun 34:
2387; l) Yang YH, Shi M (2005) Tetrahedron Lett
46: 6285; m) Dabiri M, Salehi P, Baghbanzadeh M,
Bahramnejad M (2006) Tetrahedron Lett 47: 6983
[7] a) Hamad ASS, Hashem HI (2002) J Heterocycl Chem
39: 1325; b) Kerr VN, Ott DG, Hayes FN (1960) J Am
Chem Soc 82: 186
[8] Borg S, Vollinga RC, Labarre M, Payza K, Terenius L,
Luthman K (1999) J Med Chem 42: 4331
[9] Carlsen PHJ, Jorgensen KB (1994) J Heterocycl Chem
31: 805
[10] Short FW, Long LN (1969) J Heterocycl Chem 6: 7
[11] Reddy CK, Reddy PSN, Ratnam CV (1983) Synthesis
842
[12] Spiros L, Allen MP, Segelstein BE (2000) Synth Com-
mun 30: 437
2-(3-Nitrophenyl)-1,3,4-oxadiazole (3h, C8H5N3O3)
Mp 125–126ꢂC; IR (KBr): ꢀꢀ¼ 1611 (C¼N), 1524, 1462,
1059 cmꢄ1; 1H NMR (CDCl3, 300 MHz): ꢁ ¼ 7.75–8.59 (m,
4H, Ar–H), 8.93 (s, CH) ppm; 13C NMR (CDCl3, 75 MHz):
ꢁ ¼ 122.06, 125.19, 126.43, 130.57, 132.68, 148.66,
174.81 ppm; MS: m=z (%) ¼ 191 (Mþ, 100), 150 (48), 117
(25), 90 (78).
2-Methyl-5(3-nitrophenyl)-1,3,4-oxadiazole (3i, C9H7N3O3)
Mp 156–158ꢂC; IR (KBr): ꢀꢀ¼ 1586, 1561, 1467, 1062 cmꢄ1
;
1H NMR (CDCl3, 300 MHz): ꢁ ¼ 2.68 (s, CH3), 7.71–8.84
(4H, m, Ar–H) ppm; 13C NMR (CDCl3, 75MHz): ꢁ ¼
111.69, 121.63, 125.57, 126.01, 130.42, 132.28, 148.61,
163.61, 164.54 ppm; MS: m=z (%) ¼ 205 (Mþ, 100), 150
(48), 104 (32), 76 (30), 15 (45).
2-Phenyl-1,3,4-oxadiazole (3l, C8H6N2O)
Mp 150–152ꢂC; IR (KBr): ꢀꢀ¼ 1598, 1574, 1481, 1070, 712,
691 cmꢄ1; 1H NMR (DMSO-d6, 300 MHz): ꢁ ¼ 7.45–7.83 (m,
5H, Ar–H), 8.10 (s, CH) ppm; 13C NMR (CDCl3, 75 MHz):
ꢁ ¼ 127.91, 128.93, 129.05, 132.34, 160.39, 165.69 ppm; MS:
m=z (%) ¼ 147 (M þ 1, 25), 146 (Mþ, 22), 105 (100), 77 (100).
2-Ethyl-5-phenyl-1,3,4-oxadiazole (3m, C10H10N2O)
[13] Rigo B, Cauliez P (1986) Synth Commun 16: 1665
[14] a) Brain CT, Paul JM, Loong Y, Oakley PJ (1999)
Tetrahedron Lett 40: 3275; b) Brain CT, Brunton SA
(2001) Synlett 382; c) Brown B, Clemens I, Neesom JK
(2000) Synlett 131
Mp 104–105ꢂC; IR (KBr): ꢀꢀ¼ 1573, 1533, 1483, 1057,
795, 689cmꢄ1; 1H NMR (CDCl3, 300 MHz): ꢁ ¼ 1.12 (t, J ¼
6.75Hz, CH3), 2.31 (q, J ¼ 6.75 Hz, CH2), 7.34–7.784 (m, 5H,
Ar–H) ppm; 13C NMR (CDCl3, 75MHz): ꢁ ¼ 9.61, 27.33,
127.57, 128.65, 131.31, 132.38, 165.38, 172.64 ppm; MS:
m=z (%) ¼ 174 (Mþ, 45), 136 (23), 105 (100), 77 (73), 51 (23).
[15] a) Ainsworth C (1955) J Am Chem Soc 77: 1148; b)
Leiby RW (1984) J Heterocycl Chem 21: 1825; c) Shafiee
A, Naimi E, Mansobi P, Foroumadi A, Shekari M (1995)
J Heterocycl Chem 32: 1235; d) Khajavi MS, Sadat
Hosseini SS, Sefidkon F (1997) Iran J Chem Chem
Eng 16: 68; e) Dabiri M, Salehi P, Baghbanzadeh M,
Bahramnejad M (2007) Synth Commun 37: 1201
[16] Tanaka K, Toda F (2000) Chem Rev 100: 1025
[17] a) Dabiri M, Salehi P, Mohammadi AA, Baghbanzadeh
M (2005) Synth Commun 35: 279; b) Salehi P, Dabiri M,
Baghbanzadeh M, Bahramnejad M (2006) Synth Com-
mun 36: 2287; c) Dabiri M, Salehi P, Mohammadi AA,
Baghbanzadeh M, Kozehgiry G (2004) J Chem Res (S)
570; d) Salehi P, Dabiri M, Zolfigol MA, Bodaghi Fard
MA (2003) Tetrahdron Lett 44: 2889; e) Salehi P, Dabiri
M, Zolfigol MA, Baghbanzadeh M (2005) Synlett 1155;
f) Salehi P, Dabiri M, Khosropour AR, Roozbehniya P
(2006) J Iran Chem Soc 3: 98; g) Salehi P, Dabiri M,
Zolfigol MA, Baghbanzadeh M (2005) Tetrahedron Lett
46: 7051; h) Salehi P, Dabiri M, Zolfigol MA, Otokesh S,
Baghbanzadeh M (2006) Tetrahedron Lett 47: 2557; i)
Baghbanzadeh M, Salehi P, Dabiri M, Kozehgary GH
(2006) Synthesis 344; j) Dabiri M, Salehi P, Zolfigol
MA, Baghbanzadeh M (2007) Heterocycles 71: 677
[18] a) Dabiri M, Salehi P, Baghbanzadeh M, Kiani S,
Acknowledgement
Financial support by the Research Council of Shahid Beheshti
University and CCE is gratefully acknowledged.
References
[1] a) Ates O, Kocabalkanli A, Sanis GO, Ekini AC, Vidin A
(1997) Drug Res 47: 1134; b) Dabhi TP, Shah VH, Parikh
AR (1992) Indian J Pharm Sci 54: 98; c) Hui XP, Zhang
LM, Zhang ZY, Wang Q, Wang F (1999) Indian J Chem
Sect B Org Chem Incl Med Chem 38: 1066
[2] a) Holla BS, Gonsalves R, Shenoy S (2000) Eur J Med
Chem 35: 267; b) Cesur N, Birteksoz S, Otuk G (2002)
Acta Pharm Turcica 44: 23; c) Laddi UV, Desai SR,
Bennur RS, Bennur SC (2002) Indian J Heterocycl
Chem 11: 319
[3] Tyagi M, Kumar A (2002) Oriental J Chem 18: 125
[4] Zheng X, Li Z, Wang Y Chen W, Huang Q, Liu C,
Song G (2003) J Fluorine Chem 123: 163
[5] Zou XJ, Lai LH, Jin GY, Zhang ZX (2002) J Agric Food
Chem 50: 3757
[6] a) Rigo B, Fassuer D, Cauliez P, Couturier D (1989)
Synth Commun 19: 2321; b) Rigo B, Cauliez P, Fasseur
D, Couturier D (1988) Synth Commun 18: 1247; c)
Singh SP, Naithani R, Batra H, Prakash O, Sharma D
(1998) Indian J Heterocycl Chem 8: 103; d) Froeyen P
Vakilzadeh Y (2007) Monatsh Chem 138: (in
press); b) Azizian J, Mohammadi AA, Karimi AR,
Mohammadizadeh MR (2005) J Org Chem 70: 350
[19] Rostamizadeh S, Ghasem Housaini SA (2004) Tetrahe-
dron Lett 45: 8753