Efficient and convenient protocol for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles using HClO4-SiO2 as a heterogeneous recyclable catalyst

Article abstract of DOI:10.1080/00397911.2014.883633

Silica-supported perchloric acid (HClO₄SiO₂) was found to be a new, highly efficient, inexpensive, and reusable catalyst for a rapid and efficient synthesis of various 1,2,4-oxadiazoles with good to excellent yields under solvent-free conditions. The present methodology has been effectively utilized for the synthesis of oxolamine, an anti-inflammatory drug.

Full text of DOI:10.1080/00397911.2014.883633

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Efficient and Convenient Protocol for
the Synthesis of 3,5-Disubstituted
1,2,4-Oxadiazoles Using HClO4-SiO2 as a
Heterogeneous Recyclable Catalyst
Ramu Tadikonda a , Mangarao Nakka a , Mahaboob Basha Gajula a
, Srinuvasarao Rayavarapu a , Padma Rao Gollamudi a & Siddaiah
Vidavalur a
a Department of Organic Chemistry and Foods, Drugs and Water ,
Andhra University , Visakhapatnam , India
Accepted author version posted online: 03 Apr 2014.Published
online: 29 May 2014.
To cite this article: Ramu Tadikonda , Mangarao Nakka , Mahaboob Basha Gajula , Srinuvasarao
Rayavarapu , Padma Rao Gollamudi & Siddaiah Vidavalur (2014) Efficient and Convenient Protocol for
the Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles Using HClO4-SiO2 as a Heterogeneous Recyclable
Catalyst, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 44:13, 1978-1986, DOI: 10.1080/00397911.2014.883633
To link to this article: http://dx.doi.org/10.1080/00397911.2014.883633
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Synthetic Communications1, 44: 1978–1986, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.883633
EFFICIENT AND CONVENIENT PROTOCOL FOR
THE SYNTHESIS OF 3,5-DISUBSTITUTED
1,2,4-OXADIAZOLES USING HClO4-SiO2 AS
A HETEROGENEOUS RECYCLABLE CATALYST
Ramu Tadikonda, Mangarao Nakka, Mahaboob Basha
Gajula, Srinuvasarao Rayavarapu, Padma Rao Gollamudi, and
Siddaiah Vidavalur
Department of Organic Chemistry and Foods, Drugs and Water, Andhra
University, Visakhapatnam, India
GRAPHICAL ABSTRACT
Abstract Silica-supported perchloric acid (HClO4-SiO2) was found to be a new, highly
efficient, inexpensive, and reusable catalyst for a rapid and efficient synthesis of various
1,2,4-oxadiazoles with good to excellent yields under solvent-free conditions. The present meth-
odology has been effectively utilized for the synthesis of oxolamine, an anti-inflammatory drug.
Keywords Acid anhydrides; amidoxime; HCLO4-SiO2; 1,2,4-oxadiazole; reusable catalyst
INTRODUCTION
1,2,4-Oxadiazole scaffolds are known to possess significant biological activities,
such as anti-inflammatory,[1] antiviral,[2] antirhinoviral,[3] and antitumor[4] activities.
1,2,4-Oxadiazoles are often used in drug discovery as hydrolysis-resisting bioisosteric
replacements for ester or amide functionalities and are also used in the design of dipep-
tidomimetics as peptide building blocks. Moreover, the 1,2,4-oxadiazole motif can be
found in several drugs and drug leads including the potent S1P1 agonist (1),[5] the
metabotropic glutamate subtype 5 (mGlu5) receptor (2),[6] and muscarinic receptor[7]
for the treatment of Alzheimer’s disease. Generally, 1,2,4-oxadiazoles are synthesized
by coupling of amidoximes with (i) activated carboxylic acid derivatives such as acid
chlorides,[8] fluorides,[9] anhydrides,[10] or active ester;[11] and (ii) carboxylic acids in
Received October 22, 2013.
Address correspondence to Siddaiah Vidavalur, Department of Organic Chemistry and Foods,
Drugs and Water, Andhra University, Visakhapatnam 530 003, India. E-mail: siddaiah_v@yahoo.com
1978

SYNTHESIS OF 1,2,4-OXADIAZOLES
1979
the presence of coupling reagents including dicyclohexylcarbodiimide (DCC),[10b,12]
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC),[8a,10a,13] 2-(dimethylamino)
propyl chloride (DIC)=HOBt,[9] bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-
Cl),[10b] 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU),[14]
or 1,10-carbodiimidazole (CDI)[15] followed by cyclodehydration.[16] Other methods to
obtain 1,2,4-oxadiazoles include reaction of amidoximes with aryl halides in the presence
of palladium catalysts[17] or with aldehydes followed by oxidation.[18] However, these
methods always suffered from the limitation of harsh conditions, tedious synthetic
procedures, long reaction times, and expensive reagents or solvents. Therefore,
developing a milder and general procedure to access 1,2,4-oxadiazoles is still highly
desirable.
In recent years, heterogeneous catalysts have gained prominence because of
environmental and economic considerations.[19] They have successfully been utilized
in several organic transformations to minimize undesirable waste that causes
environmental pollution. To the best of our knowledge, no report on the use of
silica-supported perchloric acid (HClO4-SiO2) as a catalyst utilizing carboxylic acid
anhydrides is known for the synthesis of 3,5-disubtituted 1,2,4-oxadiazoles. As a part
of our ongoing research program[20] on the development of efficient and environmen-
tally benign synthetic protocols for the synthesis of heterocycles, herein we report
a simple and efficient one-pot method for the synthesis of 3,5-disubstituted 1,2,4-
oxadiazoles from amidoximes and acid anhydrides using silica-supported perchloric
acid (HClO4-SiO2) at 80 ꢀC under solvent-free conditions (Scheme 1).
RESULTS AND DISCUSSION
Initially, a mixture of benzamidoxime (3a, 1.47 mmol) and acetic anhydride
(4a, 1.77 mmol) was heated at 80 ꢀC under solvent-free conditions in the presence
of different catalysts such as activated SiO2, NaHSO4-SiO2, p-toluenesulfonic acid
(p-TSA)–SiO2, amberlyst-15, and HClO4-SiO2 (5 mol% each) separately. Activated
SiO2, NaHSO4-SiO2, p-TSA-SiO2, and amberlyst-15 catalyze the reaction to furnish
the desired product 5a, albeit in poor yields (Table 1, entries 3–6). To our delight,
HClO4-SiO2 gave the desired 3,5-disubstituted 1,2,4-oxadiazole 5a in 95% yield
(Table 1, entry 9). Encouraged by this result, we then focused on optimizing the reaction
Scheme 1. Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles.

1980
R. TADIKONDA ET AL.
Table 1. Optimization of reaction conditions
Entry
Catalyst
Amount of catalyst (mol %) Temperature (ꢀC) Time (min) Yield (%)a
1
2
—
—
—
—
5
rt
80
300
120
90
60
30
3
15
40
55
60
65
68
25
79
95
90
85
87
80
3
Activated SiO2
NaHSO4-SiO2
p-TSA-SiO2
Amberlyst-15
HClO4-SiO2
HClO4-SiO2
HClO4-SiO2
HClO4-SiO2
HClO4-SiO2
HClO4-SiO2
HClO4-SiO2
80
80
4
5
5
5
80
80
6
5
7
5
Rt
50
180
20
5
8
5
9
5
80
10
11
12
13
5
100
120
80
5
5
5
10
1
5
30
80
aIsolated yield.
conditions. The HClO4-SiO2 loading was subsequently examined (Table 1, entries 9, 12,
and 13), and it was found that 5 mol% of HClO4-SiO2 provides the maximum yield in
the least time (Table 1, entry 9). We immediately undertook a study to examine the
effects of temperature on this transformation (Table 1, entries 7, 8, 10, and 11). The
results demonstrated that 80ꢀC appeared to be the optimum temperature for this trans-
formation. Thus, the best yield, cleanest reaction, and most facile workup were achieved
by employing 5 mol% of HClO4-SiO2 at 80 ꢀC under solvent-free conditions (Table 1,
entry 9).
To generate a small library of functionalized 1,2,4-oxadiazoles (5), we next
utilized a variety of substrates to explore the synthetic scope and generality of this
method under the optimal conditions (Table 2). Notably, a wide range of anhydrides
(4a–h) and amidoximes (3a and 3b) were well tolerated and proceeded smoothly
under the optimized reaction conditions. All products obtained were characterized
1
by spectroscopic methods such as H NMR, 13C NMR, and mass spectrometry.
Next, we investigated the reusability of HClO4-SiO2. A mixture of benzami-
doxime, acetic anhydride, and HClO4-SiO2 was stirred at 80 ꢀC for 5 min. After
the completion of the reaction (monitored by thin-layer chromatography, TLC),
the reaction mixture was diluted with dichloromethane (DCM, 5 mL) and the
catalyst was separated by simple filtration. The recovered catalyst was activated
and reused for three consecutive times with only slight variation in the yields of
the products (93%, 92%, and 90%).
Substituted oxadiazoles are present in many important pharmaceutically active
molecules. Although many of the compounds in Table 2 already display drug like
attributes, we wanted to demonstrate the utility of this method through the synthesis
of a pharmaceutically relevant molecule oxolamine, an anti-inflammatory drug.
Thus, benzamidoxime (3a) was treated with 3-chloropropanoic anhydride in the
presence of HClO4-SiO2 under solvent-free conditions to get compound 6. Subsequently,
it was treated with commercially available Et2NH ꢁ HCl in the presence of K2CO3 under
refluxing conditions to afford desired oxolamine (7) in 84% yield (Scheme 2).

SYNTHESIS OF 1,2,4-OXADIAZOLES
1981
Table 2. HClO4-SiO2-catalyzed synthesis of 3,5-disubstituted 1,2,4-oxadiazoles
Time
(min)
Yield
(%)a
Entry
Amidoxime (3)
Anhydride (4)
Product (5)
1
5
95
95
95
94
2
3
4
4a
5
5
6
4b
5
6
5
5
95
94
4c
7
4
96
(Continued )

1982
Entry
8
R. TADIKONDA ET AL.
Table 2. Continued
Time
(min)
Yield
(%)a
Amidoxime (3)
Anhydride (4)
Product (5)
4d
5
95
9
6
96
10
11
12
13
4e
5
7
7
8
95
92
93
86
4f
14
4g
8
83
(Continued )

SYNTHESIS OF 1,2,4-OXADIAZOLES
1983
Table 2. Continued
Time
(min)
Yield
(%)a
Entry
Amidoxime (3)
Anhydride (4)
Product (5)
15
7
91
16
4h
8
90
aIsolated yield.
Scheme 2. Reagents and conditions: (a) 3-chloropropanoic anhydride, HClO4-SiO2, solvent-free, 80 ꢀC,
8 min; (b) K2CO3, KI, CH3CN, Et2NH.HCl, reflux, 3 h.
The advantage of this method over previous methods could be established
while comparing the results obtained with acetic anhydride as well as with hexanoic
anhydride. For instance under the reaction condition with benzaldehyde and with
ammonium acetate and nitroethane in acetic acid under reflux conditions to afford
5-methyl-3-phenyl-1,2,4-oxadiazole (5a) the reported yield is 50%,[21] whereas the
same product could be obtained in 95% yield within 5 min under the method
described on this report. On the other hand, the reaction of benzamidoxime
with hexanoic anhydride in water under reflux conditions resulted in 53% yield of
the 5-pentyl-3-phenyl-1,2,4-oxadiazole (5g) in 12 h,[22] whereas the present method
affords 96% yield of the corresponding product in 4 min.
EXPERIMENTAL
General Experimental Procedure for 5-Methyl-3-phenyl
1,2,4-oxadiazole (Table 2, 5a)
A mixture of benzamidoxime (1.47 mmol), acetic anhydride (1.77 mmol), and
HClO4-SiO2 (5 mol%) was stirred at 80 ꢀC for the specified time (Table 2). After
completion of the reaction as indicated by TLC, the mixture was cooled to room
temperature and diluted with DCM, and the catalyst was allowed to settle down.

1984
R. TADIKONDA ET AL.
Then the reaction mixture was filtered and washed with DCM, and the combined
organic layers were washed with saturated aqueous NaHCO3 and water. The
obtained organic layer was dried over anhydrous Na2SO4 and concentrated under
reduced pressure to get crude compound 5a, which was further purified by column
chromatography on silica gel using hexane=EtOAc as eluents.
1
Mp 35–37 ꢀC; H NMR (400 MHz, DMSO-d6): d 2.63 (s, 3H), 7.50–7.57 (m,
3H), 7.98–8.00 (m, 2H); 13C NMR (100 MHz, DMSO-d6): d 11.8, 126.3, 126.8,
129.0, 131.2, 167.6, 177.2; LC-MS: m=z 161 [M þ H]þ. Anal. calcd. for C9H8N2O:
C, 67.49; H, 5.03; N, 17.49. Found: C, 67.44; H, 5.09; N, 17.45.
CONCLUSIONS
In summary, we have developed a simple, efficient, and ecofriendly method for
the synthesis of 3,5-diubstituted 1,2,4-oxadiazoles using HClO4-SiO2. The protocol
uses amidoximes and acid anhydrides as starting materials, and the corresponding
products were obtained in fair to excellent yields at 80 ꢀC under solvent-free con-
ditions. The HClO4-SiO2 catalyst was reused for three consecutive times with only
a slight variation in yields of the products. The present methodology has been
effectively utilized for the synthesis of oxolamine, an anti-inflammatory drug.
ACKNOWLEDGMENTS
We sincerely thank Sri G. Ganga Raju, chairman, and G. Rama Raju, director,
Laila Impex, for analytical support.
FUNDING
The authors thank the Department of Science and Technology, New Delhi, for
financial assistance (through Project SR=FT=CS-052=2008) and the University
Grants Commission, New Delhi, for the award of junior research fellowships to
T. Ramu and N. Mangarao.
SUPPORTING INFORMATION
Full experimental details and 1H and 13C NMR spectra can be accessed on the
publisher’s website.
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