Microwave promoted one-pot synthesis of 2-aryl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazole derivatives using Al3+-K10 clay as a heterogeneous catalyst

Article abstract of DOI:10.1016/j.tetlet.2014.05.004

An efficient, inexpensive method is developed for the one-pot synthesis of 2-aryl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles starting from acid hydrazides and trimethyl orthoformate under solvent-free, microwave conditions using a reusable Al

Full text of DOI:10.1016/j.tetlet.2014.05.004

Accepted Manuscript
Microwave promoted one-pot synthesis of 2-aryl substituted 1,3,4-oxadiazoles
and 1,2,4-oxadiazole derivatives using Al3+-K10 clay as a heterogeneous cata-
lyst
Dhanusu Suresh, Kuppusamy Kanagaraj, Kasi Pitchumani
PII:
S0040-4039(14)00780-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.004
TETL 44594
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 March 2014
2 May 2014
3 May 2014
Please cite this article as: Suresh, D., Kanagaraj, K., Pitchumani, K., Microwave promoted one-pot synthesis of 2-
aryl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazole derivatives using Al3+-K10 clay as a heterogeneous catalyst,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.004
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Microwave promoted one-pot synthesis of 2-aryl substituted 1,3,4-oxadiazoles and
1,2,4-oxadiazole derivatives using Al3+-K10 clay as a heterogeneous catalyst
Dhanusu Suresh,a Kuppusamy Kanagaraj,a and Kasi Pitchumani*a,b
aSchool of Chemistry, Madurai Kamaraj University, Madurai 625012, India
bCentre for Green Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai
625012, India
E-mail : pit12399@yahoo.com
Abstract
An efficient, inexpensive method is developed for the one-pot synthesis of 2-aryl
substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles starting from acid hydrazides and
trimethyl orthoformate under solvent-free, microwave conditions using a reusable Al3+-K10
montmorillonite clay as heterogeneous catalyst. The novelty of the present study lies in the
synthesis of oxadiazole and benzimidazole moieties in a one-pot process in high yield from
easily available precursors and catalysts under mild conditions.
Keywords: K10-Montmorillonite; 1,3,4-oxadiazoles; 1,2,4-oxadiazoles; one-pot solvent-free
synthesis; Green Protocol.
1

Heterocyclic compounds are very important class of organic compounds and in
particular oxadiazole derivatives receive much attention because of their applications in drug
discovery.1a-c Often, these molecules are used as pharmacophores due to their metabolic
stability, ability to bind with target peptides and can be engaged in hydrogen bond
formation.2 They have activities like anti-fungal, antimicrobial,3 anti-hypertensive4 and
antituberculosis.5 They are also useful as inhibitors of bacterial phenylalanyl-tRNA
synthetase,6 human neutrophil elastase,7 antagonists,8,9 y-secretase inhibitor,10
antikinetoplastid activity,11 cancer cell proliferation12 and orientation in the γ-aminobutyric
acid binding site.9 In addition, they are known as inhibitors of cathepsin K,13 and found as
astrocyte differentiation enhancement in rat fetal neural stem cells.14
Synthesis of 1,3,4-oxadiazoles has been reported by the cyclization of acid hydrazides
under strong acid conditions.15 This heterocyclic compound has also been synthesized from
diacylhydrazines, semicarbazide and thiocarbzide in the presence of dehydrating agents such
as
phosphorusoxychloride,16
(O-benzotiazol-1-yl)-N,N,N’,N’-tetramethyluranium
tetrafluoroborate) TBTU,17 molecular iodine,18 and polymer supported reagents.19-21 1,3,4-
Oxadiazoles was also synthesized in high temperature/high pressure in continuous flow
method22
and the reaction between (N-isocyamino)triphenylphosphorane with acid
derivatives.23 On the other hand, the reaction between acid hydrazides and orthoesters
resulted in the formation of 1,3,4-oxadiazoles under harsh condition, use of excess
orthoformate and longer reaction time24-25. This strategy was modified by use of catalyst
such as BF3.EtO,26 orthophosphoric acid,15 silica sulphuric acid,27 acetic acid28 and solid
®
supported Nafion NR50.29a These reported methods suffer from any one or more of the
following drawbacks like expensive homogeneous catalysts, requires strong acidic
conditions, long reaction times, low yields of the products, tedious work-up procedure, and
the reagents are toxic in nature. With a view to develop environmentally benign protocols,29b-
2

h
the present study aims to develop a facile one-pot synthesis of 1,3,4-oxadiazole and 1,2,4-
oxadiazole derivatives from acidhydrazide with orthoesters and also from amidoxime with
orthoesters using Al3+-K10 clay as a heterogeneous catalyst under solvent-free, microwave
conditions.
The reaction conditions were optimized in the one-pot synthesis of 2-(4-
methoxyphenyl)-1,3,4-oxadiazole (3i) using 4-methoxybenzhydrazide (1i) and
trimethylorthoformate (2a) as substrates. The observed results are presented in Table 1.
Control experiments showed the absence of product (Table 1, entries 1 and 2) under thermal
and MW heating indicating the requirement of a catalyst to promote this transformation. On
the other hand, catalysts like AlCl3, Al2O3, CuCl and TiCl4 (Table 1, entries 3-6) resulted in
o
56, 39, 29 and 67 % yield of 3i under MW irradiation at 55 C in 15 min. In addition, Cu2+,
Zn2+ and Ti4+-exchanged K10 clays resulted 71, 83 and 90 % yields respectively (Table 1,
entries 7-9) under MW irradiation in 15 min. On the other hand Al3+-K10 clay showed 65 %
yield in toluene at 55 oC in 2.5 h while the same catalyst yielded 90 % of the product 3i under
o
neat conditions by heating at 55 C in 45 min. Further, when the reaction was carried out at
room temperature with Al3+-K10 clay as catalysts yields 17 % of the desired product (3i)
o
(Table 1, entry 10). Increase in temperature from 40 and 55 C under MW conditions
o
accelerates the reaction and further increase the temperature to 100 C under MW condition
no significant increase in yield (Table 1, entries 13-15). Also, it is interesting to note that
o
Al3+-K10 clay exhibited 96 % of the product 3i under MW irradiation at 55 C in 15 min
(Table 1, entry 14). It was observed that Al3+-K10 catalyst under MW irradiation at 55 oC for
15 min with various organic solvents exhibited in lower yields of the product 3i (Table 1,
entries 13-18). This gives an additional advantage to the present protocol where it does not
require any solvent, reaction gets completed in a short span of time and non-conventional
energy source namely MW irradiation is used as an alternative source. On the other hand, a
3

three dimensional porous aluminosilicate namely HY zeolite yielded 64 % of the desired
product 3i under identical reaction conditions with MW. Further reducing the loading of 2a
from 3 equiv. to 1.5 equiv. lowered the yield from 96 to 49 % respectively. In addition, the
catalyst loading also influenced the yield of the product. For example, use of 25 and 50 mg of
Al3+-K10 catalyst resulted in 24 and 62 % yields whereas 75 mg showed 96 % yield under
the same conditions.
Table 1
After optimizing the catalyst loading, time, heating method and catalyst for the
synthesis of 2-substituted 1,3,4-oxadiazole in very high yield, we extended this protocol for
the synthesis of various 2,5-disubstituted 1,3,4-oxadiazoles starting from the corresponding
acid hydrazides with 2a or trimethyl orthoacetate (2b). The observed results are summarized
in Table 2.
Table 2
Reasonably high yields (85-96 %) were observed with acid hydrazides containing
electron withdrawing or electron donating substituents. Interestingly, acid hydrazide with
disubstituted groups also resulted in high yields with 2a (Table 2, entries 10-12). Increasing
the size of the acid hydrazide showed no influence on yield (Table 2, entry 7). On the other
hand, replacing 2a by 2b exhibited high yields with various substituted acid hydrazides and
4

the observed results are given in Table 2.37 These experiments have clearly shown that the
process is highly efficient and clean as the observed product only is 2,5-disubstituted 1,3,4-
oxadiazole in high yields.
The efficiency of this protocol was further extended to synthesize another set of 2,5-
disubstituted 1,3,4-oxadiazole derivatives. Various substituted acid hydrazides were treated
with 2b, triethyl orthopropionate (2c), trimethyl orthobutyrate (2d), triethyl orthovalerate
(2e) and triethyl orthobenzoate (2f) under the optimized reaction conditions resulting in the
corresponding 2,5-disubstituted 1,3,4-oxadiazole (3u-ad) derivatives in high yields. The
observed results are presented in Table 3.37
Table 3
These interesting results have prompted us to construct oxadiazole and benzimidazole
in the same molecule through one-pot synthesis starting from acid hydrazide containing 1,2-
diamino groups with excess trimethyl orthoesters (2a-f) under the optimized conditions. The
observed results are given in Table 4.37 It is evident from this table that this methodology can
be easily applied to synthesize various heterocycles containing oxadiazole and benzimidazole
moieties (4a-f) simultaneously in high yields (~ 90 %).
Table 4
To ascertain the formation of oxadiazole, structure of 4c (Table 4) was solved by single
crystal X-ray diffraction (Figure S4) which confirms the presence of benzimidazole and
oxadiazole moieties in the synthesized molecule. These examples clearly illustrate that use of
5

Al3+-K10 clay can be conveniently used as a green solid acid catalyst, for the construction of
nitrogen heterocycles in high yields.
After having demonstrated the catalytic activity of Al3+-K10 as superior catalyst for
the synthesis of 1,3,4-oxadiazoles, we are prompted to explore the synthesis of isomeric
1,2,4-oxadiazoles. To our surprise, the optimized reaction conditions allowed us to synthesize
a series of 3-substituted 1,2,4-oxadiazoles (6a-f) were synthesized starting from substituted
amidoximes (5a-f) and 2a in the presence of Al3+-K10 clay as catalysts in high yields. The
observed results are given in Table 5.38
Table 5
The data clearly show that the present methodology leads to the synthesis of various
3-substituted 1,2,4-oxadiazoles containing various functional groups and presence of electron
donating/electron withdrawing substituents have no influence on the yield of the products. In
addition, this procedure allows to synthesize 1,2,4-oxadiazole moiety bearing heterocyclic
unit such as substituted pyridyl in the 3rd position demonstrating that this protocol can be
utilized for the facile construction of various 1,2,4-oxadiazoles using an environmentally
benign catalyst in high yields.
Reusability experiments were performed between acid hydrazide and trimethyl
orthoformate as substrates using Al3+-K10 clay as catalyst and it was observed that the
catalyst can be used atleast five times with only a slight decrease in yield (Table 6) which can
be attributed to loss of catalyst while recycling.
Table 6
6

Scheme 1
To test that the methodology does not affect the integrity of stereogenic centers, Boc
protected L-proline was used to prepare the hydrazide, which was treated with trimethyl
orthoformate to give 2-substituted-1,3-4,-oxadiazole (Scheme 1). Specific Optical Rotation
results confirmed that this methodology does not affect the integrity of stereogenic center.
SFC chiral purity report also confirmed the formation of a single stereoisomer.
Based on the reported literature reports,15, 17, 18, 20, 21, 24-29, 36 a plausible mechanism is
proposed for the formation of 1,3,4-oxadiazoles (Scheme 2). Initially Al3+ binds to the
oxygen atoms in trialkyl orthoester and forms reactive intermediate (I) which readily loses an
alcohol molecule. When electron rich nitrogen from hydrazide approaches the electron
deficient carbon center, intramolecular cyclization is facilitated, leading to loss of another
molecule of alcohol. Subsequent elimination of hydrogen and O-alkyl group from the cyclic
intermediate (II) leads to aromatization and release of the heterocyclic 1,3,4-oxadiazole.
Scheme 2
A similar route is also proposed to rationalize the formation of 1,2,4-oxadiazoles
(scheme 3).
Scheme 3
7

Data on the reaction conditions, as well as the activity and efficiency of the different
catalysts reported in literature for the synthesis of 2-substituted 1,3,4-oxadiazoles and
1,2,4-oxadiazole derivatives are given in Table 7. These reported catalytic systems have their
own advantages and disadvantages. These catalytic systems involve hazadous Lewis acid
catalysts and some of them transition-metal-mediated catalytic processes, and the catalysts
are not easy to recover by simple filtration. Taking all these into account, the use of Al3+-K10
clay as catalyst which not only generates less waste but also has several advantages, which
includes insolubility in water / organic solvent, good catalytic activity and high thermal
stability. It is also nontoxic, environmentally benign, milder, cheap and exhibit wider
substrate scope with higher selectivity and improved product yields. Al3+-K10 clay catalyst
can also be easily recovered by simple filtration and reused for many times without
significant change of its activity. The catalyst is commercially available and easy to prepare
and handle. It is evident that the present system enjoys many advantages like reusability
without much decrease in the yield, use of green solid acid catalyst and a non-conventional
energy source namely MW, and requires no additional solvent for the synthesis of the
heterocyclic compounds.
Table 7
In summary, we have developed a novel protocol for the one-pot solvent-free
synthesis of 2-substituted 1,3,4- and 1,2,4-oxadiazole derivatives using a reusable, non toxic,
cheap, metal-exchanged clay (Al3+-K10 clay) as the heterogeneous catalyst. The present
methodology can also be successfully applied for the synthesis of heterocyclic compounds
bearing oxadiazole and benzimidazole moieties simultaneously in a one-pot synthesis.
8

Acknowledgments
KP thanks the Department of Science and Technology, New Delhi, India and ADM
thanks the University Grants Commission, New Delhi for the award of Assistant
Professorship under its Faculty Recharge Programme. K.K. thanks the Council of Scientific
and Industrial Research, New Delhi for the award of Senior Research Fellowship.
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37. General procedure for the synthesis of 1,3,4-oxadiazole derivatives : A 5 mL
microwave vial was charged with acidhydrazide (100 mg, 1 equiv.), trimethyl
orthoester (2 equiv.) and Al3+-K10 clay (75 mg). The resulting mixture was kept under
0
microwave irradiation maintaining the temperature at 55 C for 15 min (Microwave
irradiations were performed on CEM-discover model No. 908010). The reaction was
monitored by TLC. After completion of the reaction, reaction mixture was diluted with
ethyl acetate stirred well, filtered, washed well with ethyl acetate. Filtrate was
evaporated under reduced pressure to obtain highly pure product. In some cases,
products were purified by column chromatography using 60-120 mesh silica with 20-
100 % ethyl acetate in petroleum ether as eluents. The catalyst recovered by filtration
was reused for consecutive runs.
38. General procedure for the synthesis of 1,2,4-oxadiazole :
A 5 mL microwave
vial was charged with amidoxime (100 mg, 1 equiv.), trimethyl orthoester (0.2 ml, 3
equiv.) and Al3+-K10 clay (75 mg). The above procedures were followed to obtain
products in high purity. Microwave irradiations were performed on CEM-discover
model No. 908010.
12

Tables
Table 1. Optimization of reaction conditions in the one-pot synthesis of
2-(4-methoxyphenyl)-1,3,4-oxadiazole.a
S.No
1
2
3
4
5
6
7
8
Catalyst
-
-
AlCl3
Al2O3
Solvent
Toluene
-
-
Neat
-
-
-
Temp (0C)
55
Time (min)
150
15
15
15
15
15
15
15
Yieldb (%)
-
55, MW
55, MW
55, MW
55, MW
55, MW
55, MW
55, MW
55, MW
RT
-
56
39
29
67
71
83
90
17
65
90
63
96
96
61
46
33
29
61
27
64
49
24, 62
12
CuCl
TiCl4
Cu2+-K10
Zn2+-K10
Ti4+-K10
Al3+-K10
Al3+-K10
Al3+-K10
Al3+-K10
Al3+-K10
Al3+-K10
Al3+-K10
Al3+-K10
Al3+-K10
Al3+-K10
Al3+-K10
Al3+-K10
HY
-
-
-
9
15
10
11c
12
13
14
15
16c
17
18
19
20
21
22
23c
24d
25
300
150
45
15
15
15
15
15
15
15
15
15
15
15
15
15
Toluene
-
-
-
55
55
40, MW
55, MW
100, MW
55, MW
55, MW
55, MW
55, MW
55, MW
55, MW
55, MW
55 MW
55 MW
55 MW
-
Toluene
CAN
THF
1,4-Dioxane
Methanol
DMF
-
-
-
-
Al3+-K10
Al3+-K10
K10
aReaction conditions: 4-Methoxybenzhydrazide 1i (100 mg, 1.0 equiv.), trimethyl
orthoformate 2a (3.0 equiv.), Al3+-K10 clay (75 mg), solvent (1 ml used for entries 1, 4, 10,
13-18), 55 0C. bIsolated yield. cYield of the product with 1.5 equiv. of trimethyl orthoformate
is used. dYield of the reaction carried out with 25 and 50 mg of catalyst respectively.
13

Table 2. One-pot synthesis of 2,5-disubstituted 1,3,4-oxadiazole using Al3+-K10 clay as
heterogeneous catalyst.a
O
O
R
N
N
NH2
+
O
O
Ar
N
R
H
O
Ar
1a-m
2a-b
3a-t
Entry
Ar
R
Product
Yieldb (%)
1
2
3
4
2-F-C6H4-
4-F-C6H4-
3-Cl-C6H4-
4-Br-C6H4-
3-NO2-C6H4-
3-CF3-C6H4-
4-CH3CONH-C6H4-
3-CH3O-C6H4-
4-CH3O-C6H4-
2,4-Cl2-C6H3-
2,5-Cl2-C6H3-
3,5-(OH)2-C6H3-
2-F-C6H4-
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
92
94
89
93
5c
6
92
90
91
93
96
93
91
93
92
94
91
90
92
92
94
90
7
8
9
10
11
12c
13
14
15
16
17
18
19
20
4-F-C6H4-
3-Cl-C6H4-
3-CF3-C6H4-
4-CF3-C6H4-
3-CH3O-C6H4-
4-CH3O-C6H4-
2,5-Cl2-C6H3-
3s
3t
aReaction conditions: Acid hydrazide (1a-m) (100 mg,1 equiv.), trimethyl orthoformate (2a)
or trimethyl orthoacetate (2b) (3.0 equiv.), Al3+-K10 clay (75 mg), 55 C, and MW, 15 min.
bIsolated yield. cReaction carried with excess of 2a.
0
14

Table 3. One-pot synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives.a
O
O
N
R
N
NH2
+
R
O
O
Ar
N
H
O
Ar
1(e, l)
2b-f
3u-ad
Run
1
2
3
4
5
6
7
8
Ar
R
-CH3
Product
3u
3v
3w
3x
3y
3z
3aa
3ab
3ac
3ad
Yieldb (%)
3-NO2C6H4- (1e)
93
93
91
90
90
90
91
90
91
88
-C2H5
-n-C3H7
- n-C4H9
-C6H5
-CH3
-C2H5
-n-C3H7
-n-C4H9
-C6H5
1e
1e
1e
1e
3,5-(OH)2-C6H3- (1l)
1l
1l
1l
1l
9
10
aReaction conditions: Acid hydrazide (1e, 1l) (100 mg,1 equiv.), orthoester (2b-f)
(5.0 equiv.), Al3+-K10 clay (75 mg), 55 0C, and MW, 15 min. bIsolated yield.
Table 4. One-pot synthesis of 2,5-disubstituted 1,3,4-oxadiazole-2-yl)1H-benzo[d]imidazole
derivatives.a
N
N
O
O
R
Al3+-K10 clay
R
NH2
H2N
H2N
N
+
O
O
O
N
Neat, 55 0C
MW, 15 min
R
H
N
H
1n
2a-f
4a-f
Run
R
Product
Yieldb (%)
1
2
3
4
5
6
-H(2a)
-CH3(2b)
-C2H5(2c)
-n-C3H7(2c)
-n-C4H9(2d)
-C6H5(2e)
4a
4b
4c
4d
4e
4f
92
92
90
91
90
89
aReaction conditions: 3,4-Diaminobenzhydrazide (1n) (100 mg, 1equiv.), orthoester (2a-f)
(5.0 equiv.), Al3+-K10 clay (75 mg), 55 0C, and MW, 15 min. bIsolated yield.
15

Table 5. One-pot synthesis of 3-substituted 1,2,4-oxadiazole.a
N
Ar
O
H
O
Al3+-K10 clay
OH
N
+
H
O
O
NH2
Neat, 55 0C
MW, 15 min
N
Ar
5a-f
6a-f
2a
Entry
Ar
Product
Yieldb (%)
1
2
3
4
5
6
4-Br-C6H4-
4-OH-C6H4-
4-CH3CONHC6H4-
2-Cl-6-pyridyl-
2-Br-3-pyridyl-
3-Cl-4-CH3-C6H3-
92
91
94
93
92
92
6a
6b
6c
6d
6e
6f
aReaction conditions: Amidoxime (5a-f) (100 mg, 1eqiv.), 2a (3.0 equiv.), Al3+-K10
clay (75 mg), 55 0C, MW and 15 min. bIsolated yield.
Table 6. Reusability of Al3+-K10 clay in one-pot synthesis of 2-(4-methoxyphenyl)-1,3,4-
oxadiazole.
Run
1
2
3
4
5
Yieldb (%)
93
91
88
84
81
aReaction conditions: 4-Methoxybenzhydrazide (1i) (100 mg, 1eqiv.), 2a (3.0 equiv.), Al3+-
K10 clay (75 mg), 55 0C, and MW, 15 min. bIsolated yield.
Schemes
O
N
N
(S)
NH2
+
O
H
(S)
H
Al3+ - K10 clay
N
O
H
O
O
Neat, 55 oC, MW, 15 min.
N
N
Boc
1n
Boc
7a
2a
A name could not be
generated for this
structure.
Scheme 1. One-pot synthesis (S)-tert-butyl-2-(1,3,4-oxadiazol-2-yl)pyrrolidine-1-
carboxylate.
16

N
N
R1(OR2)3
Al3+
R
R1
O
Al3+-Clay
-R2OH
R1
O
OR2
H
N
N
R1

O
R2
R2
R


O
R2
O
(I)
Al3+
Al3+
H
R
N
NH2
O
-R2OH
H
N
NH
H
OR2
R2
R1
NH2
R2O
R1
OR2
R2
R
R2
R1
R
N
O



O
O
R2
O
O
O
R2O

Al3+
Al3+
Al3+
(II)
-R2OH
Scheme 2. Proposed mechanism for the synthesis of 2-substituted 1,3,4-oxadiazoles.
N
O
R1(OR2)3
Al3+
R
R1
N
Al3+-Clay
-R2OH
R1
O
OR2
N
O
R1

O
R2
R2
R


O
R2
N
H
Al3+
(I)
Al3+
R
N
OH
NH2
-R2OH
N
R
O
OR2
R2
R1
R1
OR2
R2
R1
R
N
N
OH
R2O
H



O
O
R2
NH2
O
O
R
R2O
2 
Al3+
Al3+
Al3+
(II)
-R2OH
Scheme 3. Proposed mechanism for the synthesis of 2-substituted 1,2,4-oxadiazoles.
17

Highlights
 Synthesis of 1,3,4- / 1,2,4-oxadiazoles using Al3+-K10 clay as catalyst
 Recovery and reuse for atleast five times
 High yield under mild conditions from easily available precursors
 Use of MW as a non-conventional energy source
 Solvent-free condition