Hypervalent iodine(V) mediated mild and convenient synthesis of substituted 2-amino-1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.tetlet.2012.05.154

A simple protocol for the synthesis of 2-amino-1,3,4-oxadiazoles starting from the corresponding acylhydrazides by cyclodesulfurization of intermediate acylthiosemicarbazides mediated by o-iodoxybenzoic acid in good yields has been described. The protocol

Full text of DOI:10.1016/j.tetlet.2012.05.154

Tetrahedron Letters 53 (2012) 4232–4234
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Hypervalent iodine(V) mediated mild and convenient synthesis of substituted
2-amino-1,3,4-oxadiazoles
⇑
Girish Prabhu, V. V. Sureshbabu
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Room No. 109, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple protocol for the synthesis of 2-amino-1,3,4-oxadiazoles starting from the corresponding acy-
lhydrazides by cyclodesulfurization of intermediate acylthiosemicarbazides mediated by o-iodoxyben-
zoic acid in good yields has been described. The protocol is mild with wide substrate scope, and thus a
range of 2-amino-1,3,4-oxadiazoles have been prepared.
Received 21 March 2012
Revised 29 May 2012
Accepted 31 May 2012
Available online 8 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hypervalent iodine reagent
IBX
Oxadiazole
Desulfurization
1,3,4-Oxadiazoles have found extensive use as pharmacophores
due to their metabolic profile and ability to engage in hydrogen
bonding. 2-Amino-1,3,4-oxadiazoles have a wide range of biologi-
cal activities such as antimicrobial agents, anti-inflammatory
agents, anticancer agents, muscle relaxants, and antimitotics,1
the 2,5-diaryl-1,3,4-oxadiazoles are known to be platelet aggrega-
tion inhibitors.2 Due to myriad of biological applications of 1,3,4-
oxadiazole scaffolds, efficient and mild methods to synthesize
these moieties have attracted considerable interest. Our research
group has recently reported simple access to 2-amino-1,3,4-oxadi-
azole peptidomimetics using p-TsCl mediated cyclization of amino
acid derived thiosemicarbazides.3 The most commonly followed
strategy involves cyclization of the corresponding acyclic semi-
carbazide4 (X = O) or thiosemicarbazide derivatives5 (X = S),
(Scheme 1). The reported protocols in the literature involve two
steps, wherein semicarbazide/acylthiosemicarbazides were syn-
thesized by reaction of hydrazides with the requisite isocyanate/
isothiocyanate, which is typically isolated and purified. In the fol-
lowing step, cyclization was carried out using an appropriate re-
agent. Most of these methods have several disadvantages such as
handling of harsh and toxic reagents, elevated temperatures, long
reaction time etc. Xie et al. has recently described an efficient cyc-
lodeselenization by heating selenosemicarbazides (X = Se) in DMF
in one-pot from isoselenocyanates and hydrazides,6 resulting in
high yields of 2-amino-1,3,4-oxadiazoles. This protocol is devoid
of the usage of any deselenizing reagent. Also there are a few
reports wherein one pot strategy was explored starting from
acylhydrazides using p-TsCl/pyridine5a and PS-carbodiimide7 and
both these methods suffer from harsh conditions which require
heating for long hours for the cyclization of the acylthiosemicar-
bazide intermediate. Thus newer and mild protocols for this privi-
leged class of molecules are continuously sought. In quest of novel
methodologies for heterocycles, we have now focused on a simple
and efficient protocol for the synthesis of 2-amino-1,3,4-
oxadiazoles.
Hypervalent iodine reagents have been extensively used in var-
ious organic transformations because of their mild oxidizing and
environmentally benign nature. The iodine atom in hypervalent
iodine(V) reagents has strong electrophilic character and with
the leaving ability of the phenyliodino group makes them reagents
of choice for various oxidative transformations.8 In addition, their
affinity for sulfur has made these reagents attractive alternatives
for desulfurization instead of heavy metal reagents.9 Recently, an
efficient synthesis of carbodiimides has been reported by desulfur-
ization of thioureas using
a variety of hypervalent iodine
reagents.9d,e We envisaged the use of o-iodoxybenzoic acid10
(IBX) as oxidative cyclization agent in the synthesis of 2-amino-
1,3,4-oxadiazoles through a possible carbodiimide intermediate.
On reviewing the mechanism of IBX oxidations, we presumed that
cyclization of semicarbazide would generate water as possible side
product, in which case the carbodiimide intermediate will revert
back to the starting semicarbazide. Whereas in case of thiosemi-
carbazide it may result in efficient cyclization with precipitation
of elemental sulfur.9 Similar would be the case for selenosemicar-
bazide, wherein cyclodeselenization using IBX may result in 2-ami-
no-1,3,4-oxadiazole with the precipitation of elemental selenium.
⇑
Corresponding author. Tel.: +91 0822961339/9986312937.
E-mail addresses: hariccb@gmail.com, sureshbabuvommina@rediffmail.com
(V.V. Sureshbabu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.154

G. Prabhu, V. V. Sureshbabu / Tetrahedron Letters 53 (2012) 4232–4234
4233
X
O
O
N N
O
R2NCX
R2 Cyclization
R2
NH2
R1
N N
N
H
R1
N
H
N
H
R1
H
H
X = O or S
Scheme 1. Two step strategies for the preparation of 2-amino-1,3,4-oxadiazoles.
envisioned that due to the polarizability of sulfur and thiophilic
nature of hypervalent iodine reagents, thiosemicarbazide could
be activated by IBX affording an intermediate which is more prone
toward cyclization (Scheme 2) and consequently we employed this
strategy for one pot synthesis of 2-amino-1,3,4-oxadiazoles di-
rectly from acylhydrazides.
1) R2NCS, CH2Cl2, rt
2) IBX, TEA, CH2Cl2, rt
N N
O
O
R2
R1
N
H
NH2
R1
N
H
One Pot
1a-1m
4a-4m
Scheme 2. One pot synthesis of 2-amino-1,3,4-oxadiazoles.
In a typical reaction, phenylisothiocyanate 1b was treated with
benzoylhydrazide 1a in CH2Cl2 at rt. After completion of reaction
(by TLC), the intermediate acylthiosemicarbazide was directly
treated with triethylamine (TEA, 2 equiv) and IBX (1 equiv) added
portion wise with continued stirring. Gratifyingly, within 15 min
the required oxadiazole was formed in 92% isolated yield.11 The
reaction conditions were optimized with respect to solvents such
as DMF, MeCN, EtOAc, THF, and equivalents of IBX and TEA. How-
ever, molar ratio of 1:1:2 for substrate/IBX/TEA in CH2Cl2 as solvent
was found to be efficient and cleaner. Lesser equivalents of TEA re-
sulted in lower yield of final product. These results encouraged us
to examine the generality of this protocol. Thus, a variety of acy-
lhydrazides and isothiocyanates were subjected to the afore-men-
tioned protocol (Table 1). In all cases complete conversion to
amino oxadiazoles in good yields and purity was obtained under
very mild conditions (Table 1, entries a–m).
Table 1
List of 2-amino-1,3,4-oxadiazoles prepared
Entry Hydrazide
Isothiocyanate Product (4)
Yielda
(%)
(1) R1
(2) R2
N N
O
a
C6H5
C6H5
92
86
N
H
N N
O
b
2-CH3C6H4
C6H5
C6H5
N
H
N N
c
3-NO2C6H4
85
N
H
O
O2N
In analogy with the literature reports of desulfurization by
hypervalent iodine reagents,9 the following mechanism (Scheme
3) was proposed for the cyclodesulfurization of acylthiosemicar-
bazides by IBX. Initially the nucleophilic attack of S on the electro-
philic iodine of IBX will form intermediate A. Then TEA assisted
desulfurization (path a) leads to carbodiimide intermediate B and
subsequent cyclization resulting in 2-amino-1,3,4-oxadiazole. In
a second pathway b, cyclization may be effected by direct nucleo-
philic attack by carbonyl oxygen assisted by TEA. The precipitation
of elemental sulfur supports the proposed mechanism.
The generality of methodology has further been demonstrated
by an example of cyclodeselenization of intermediate acylsele-
nosemicarbazide, wherein the optimized conditions were tested
for N-phenylisoselenocyanate and benzoylhydrazide 1a in CH2Cl2
at rt in one pot. As expected, cyclodeselenization was found to be
N N
O
d
e
f
4-CH3OC6H4 C6H5
83
84
83
N
H
H3CO
Cl
N
N
2-ClC6H4
3-C4H4N
C6H5
C6H5
N
O
H
N N
O
N
H
N
N
N N
O
g
h
i
4-C4H4N
C6H5
C6H5
86
84
82
N
H
N N
O
C6H5CH2
C6H11
N
H
N N
O
C6H5
N
H
O
O
N N
O
O
j
C6H5
C4H9
80
86
84
N
H
O
I
A
OH
I
O
OH
O
S
O
N N
O
O
b
S
H-NEt3
-Et3N
R2
-S
-H2O
k
l
C6H5CH2
C6H5CH2
C6H5CH2
C6H11
R2
N
R1
N N
N
H
R1
N N
N
H
H
H
H
H
a
N N
O
Et3N
3
-S
-H2O
Et3N
N
H
O
O
N N
O
R2
N
N
m
C6H5CH2
C6H5
88
R1
N N C N
H
O
O
R2
N
H
R1
N
H
I
-Et3N
O
a
H-NEt3
Et3N
Isolated yield.
B
4
H-NHEt3
Thus, we tried to explore IBX for dehydrothiolative cyclization of
acylthiosemicarbazide, to obtain 2-amino-1,3,4-oxadiazoles. We
Scheme 3. Plausible mechanism for the formation of 2-amino-1,3,4-oxadiazole 4
from thiosemicarbazide 3.

4234
G. Prabhu, V. V. Sureshbabu / Tetrahedron Letters 53 (2012) 4232–4234
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complete within 10 min of the addition of IBX, giving same product
4a. The yield was comparable to that of cyclodesulfurization at 91%
and thus, this protocol can be extended to other substrates as well.
Hence, it was evident that the IBX reagent works efficiently for
cyclodelfurization/cyclodeselenization resulting in required 2-ami-
no-1,3,4-oxadizoles in good yields and purity.
In summary, the present methodology provides a robust one-
pot approach for efficient preparation of a variety of 2-amino-
1,3,4-oxadiazoles in good yields. Important feature of this method-
ology is that the acylthiosemicarbazides were prepared in situ and
subjected to subsequent cyclization without purification using IBX
within a short duration of time, thus resulting in a hassle-free and
convenient one-pot synthesis. Thus, this strategy provides rapid
access to a wide variety of 2-amino-1,3,4-oxadiazoles under mild
conditions at room temperature.
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Acknowledgement
We gratefully acknowledge the Board of Research in Nuclear
Sciences (Grant No. 2011/37C/35/BRNS), Govt. of India for the
financial assistance.
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References and notes
11. Typical experimental procedure for the synthesis of 2-amino-1,3,4-oxadiazoles
4. Benzoyl hydrazide 1a (1.0 mmol) and phenylisothiocyanate 1b (1.0 mmol)
were combined in CH2Cl2 (5 mL) at room temperature and the resultant
solution was stirred for 3 h. Completion of the reaction was checked by TLC,
then TEA (2.0 mmol) was added under stirring, followed by addition of IBX
(1.0 mmol) portion wise and stirring was continued further for 15 min. After
completion of the reaction by TLC, the crude reaction mass was quenched with
10% NaHCO3 solution. The aqueous layer was extracted with CH2Cl2
(2 Â 10 mL). The combined organic layers were dried over anhydrous
Na2SO4, which was then admixed with silica gel and subjected to column
chromatography using EtOAc:hexane mixture as eluent to isolate the
analytically pure compound. Spectroscopic data for representative
compounds: N,5-Diphenyl-1,3,4-oxadiazol-2-amine6 (4a): Yield 92%; white
1. (a) Nofal, Z. M.; Fahmy, H. H.; Mohamed, H. S. Arch. Pharm. Res. 2002, 25, 28; (b)
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solid; mp 218 °C (lit. 218–220 °C); IR (KBr, thin film)
1562, 1498, 1442; 1H NMR (300 MHz, DMSO-d6): d 7.02 (t, J = 7.4 Hz, 1H), 7.35
(t, J = 7.6 Hz, 2H), 7.56–7.65 (m, 5H), 7.89–7.92 (m, 2H), 10.66 (br, 1H, NH); 13
m
max (cmÀ1): 3386, 3060,
3. Lamani, R. S.; Nagendra, G.; Sureshbabu, V. V. Tetrahedron Lett. 2010, 51, 4705.
4. (a) Kosmrlj, J.; Kocevar, M.; Polanc, S. Synlett 1996, 652; (b) Mazurkiewicz, R.;
Grymel, M. Pol. J. Chem. 1997, 71, 77; (c) Brain, C. T.; Paul, J. M.; Loong, Y.;
Okaley, P. J. Tetrahedron Lett. 1999, 40, 3275; (d) Brain, C. T.; Brunton, S. A.
Synlett 2001, 382; (e) Shaker, R. M.; Mahmoud, A. F.; Abdel-Latif, F. F.
Phosphorus, Sulfur and Silicon 2005, 180, 397; (f) Baxendale, I. R.; Ley, S. V.;
Martinelli, M. Tetrahedron 2005, 61, 5323; (g) Dumciute, J.; Martynaitis, V.;
Holzer, W.; Mangelinckx, S.; Kimpe, N. D.; Sackus, A. Tetrahedron 2006, 62,
3309; (h) Sharma, S.; Srivastava, V. K.; Kumar, A. Eur. J. Med. Chem. 2002, 37,
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C
NMR (100 MHz, DMSO-d6): d 117.1, 121.9, 123.9, 125.5, 129.1, 129.4, 131.0,
138.6, 159.9, 157.7; HRMS calcd for C14H11N3O m/z 237.0902, found 260.1174
[M+Na]+. N,5-Dibenzyl-1,3,4-oxadiazole-2-amine5a (4k): Yield 86%; white
solid; mp 122–123 °C (lit. 120–122 °C); IR (KBr, thin film) mmax (cmÀ1): 3334,
3032, 1548, 1468, 1422; 1H NMR (300 MHz, DMSO-d6): d 4.03 (s, 2H), 4.35 (s,
2H), 7.24 (dd, J = 7.6, 8.4 Hz, 2H), 7.28–7.30 (dd, J = 7.6, 8.4 Hz, 2H), 7.36–7.39
(m, 3H), 7.54 (m, 3H), 8.04 (t, NH); 13C NMR (100 MHz, DMSO-d6): d 163.8,
157.8, 138.9, 130.7, 129.4, 128.5, 127.6, 127.2, 125.3, 124.4, 46.1, 34.5; HRMS
calcd for C16H15N3O m/z 265.1215, found 288.1411 [M+Na]+.
5. (a) Atta, S. M. S.; Fawzy, N. M.; Ahmed, F. A.; Abdel-Rahman, A. H. Phosphorus,
Sulfur and Silicon 2002, 177, 863; (b) Wang, X. C.; Li, Z.; Wei, B. G.; Yang, J. Y.