A new and efficient synthesis of 1,3,4-oxadiazole derivatives using TBTU

Article abstract of DOI:10.1016/j.tet.2012.11.071

An efficient method for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from isothiocyanates and hydrazides through cyclodesulfurization in the presence of (O-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate) TBTU as an uronium cou

Full text of DOI:10.1016/j.tet.2012.11.071

Tetrahedron 69 (2013) 2075e2080
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new and efficient synthesis of 1,3,4-oxadiazole derivatives
using TBTU
,
Shokoofeh Maghari a, Sorour Ramezanpour a, Fatemeh Darvish a, Saeed Balalaie a
,
*
,
c
Frank Rominger b, Hamid Reza Bijanzadeh a
a Peptide Chemistry Research Center, K.N. Toosi University of Technology, PO Box 15875-4416, Tehran, Iran
b Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
c Department of Biophysics, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from isothiocyanates and
hydrazides through cyclodesulfurization in the presence of (O-(benzotriazol-1-yl)-N,N,N0,N0-tetrame-
thyluronium tetrafluoroborate) TBTU as an uronium coupling reagent has been developed. The present
methodology offers several advantages, such as simple and easy work-up procedures, mild reaction
conditions and it is environmentally benign.
Received 20 September 2012
Received in revised form 3 November 2012
Accepted 20 November 2012
Available online 28 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to Professor Firouz Matloubi
Moghaddam on the occasion of his 60th
birthday
Keywords:
1,3,4-Oxadiazole
Coupling reagent
TBTU
Hydrazides
Isothiocyanate
1. Introduction
Therefore, there is a high demand for the development of easily
accessiblemethodsforthepreparationof1,3,4-oxadiazolederivatives.
1,3,4-Oxadiazole is a versatile lead molecule for designing poten-
tial bioactive agents.1 Due to the increased hydrolytic and metabolic
stability of the oxadiazole ring, improved pharmacokinetic properties
are often observed, which make this skeleton an important structural
moiety for the pharmaceutical industry.2 Consequently, 1,3,4-
oxadiazoles have often been the target of numerous drug discovery
programs as anti-inflammatory, analgesic, antibacterial, fungicidal,
hyperglycaemic, antimalarial, antidepressant agents, and other ac-
tivities.3,4 Prescribed agents featuring the 1,3,4-oxadiazoles scaffold
include the antiretroviral isentress,5 AZD3988, which recently iden-
tified DGAT-1 inhibitors for the treatment of obesity and diabetes,6
antihypertensive nesapidil and the antibiotic furamizole7 (Fig. 1).
1,3,4-Oxadiazoles containing different functional groups have
attracted a great deal of attention from synthetic and medicinal
chemists that has led to production of novel compounds with un-
known or improved pharmacological properties. For instance,
compounds containing the 2-amino-1,3,4-oxadiazole possess bi-
ological activities such as muscle relaxants,8 and anti-mitotics9
The most straightforward synthetic route involves the cyclo-
dehydration of semicarbazides, which typically requires harsh re-
agents such as POCl310 or concentrated sulfuric acid.11 Alternatively,
phosphonium salts7 and Burgess-type reagents12 have been used to
promote the cyclization. However, these reagents cause the for-
mation of significant by-products and are only suitable for solid-
phase synthetic strategies.
When thiosemicarbazides are used as oxadiazole precursors, H2S
scavengers, suchasstoichiometricmercuric salts,13 orleadoxide,8 can
be used to affect the cyclization. Other desulfurization reagents in-
cluding I2/NaOH14 and tosyl chloride7,14b have been utilized, which
often lead to inconvenient handling and undesirable by-products.
Selective activation of the sulfur moiety followed by cyclization
has been achieved by carbodiimides (DCC,15 EDC15b,16), polymer-
supported DCC reagent17 or PS-carbodiimides.18
Disadvantages and weaknesses of these reported methods are
lack of generality, limited functional group tolerance, multistep
synthesis sequences, and harsh reaction conditions.
This paper presents a continuation of our previous work, de-
signing an efficient approach for the synthesis of 2,5-disubstituted
* Corresponding author. E-mail address: balalaie@kntu.ac.ir (S. Balalaie).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.071

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S. Maghari et al. / Tetrahedron 69 (2013) 2075e2080
Fig. 1. Prescribed agents featuring the 1,3,4-oxadiazoles scaffold.
1,3,4-oxadiazole via a desulfurization reaction of thiosemicarbazides
in the presence of coupling reagents. Thiosemicarbazide in-
termediates are obtained via reaction of hydrazides and iso-
thiocyanates (Scheme 1).
the intermolecular hydrogen bonding between the oxadiazole
rings. Fig. 2 shows the ORTEP structure of compound 4c.
It has been reported that, the presence of amide bonds in the
structure of molecule could affect its biological activity,20 to reach
(2)
(4)
O
1. DIEA
R2NCS
R2
NH
R1
O
S
2. Coupling reagent
NH2
O
N
R1
N
H
(1)
R1
NH
R2
DMF, 50 oC
HN NH
(3)
MeOH, rt
N
Scheme 1. The overall sequence to prepare 2,5-disubstituted 1,3,4-oxadiazoles.
Different coupling reagents are used for the final cyclization
including DIC, DCC as carbodiimides, TBTU as uronium coupling
reagent. TBTU is an uronium salt that acts as a highly efficient
coupling reagent commonly used in peptide chemistry for a wide
variety of peptide sequences, including the synthesis of some
pharmaceutical peptides. From an industrial and environmental
point of view, an effective coupling reagent should have the fol-
lowing characteristics: (a) high efficiency, (b) works in stoichio-
metric quantities, and (c) solubility in the currently used solvents.
Considering these characteristics, TBTU is one of the common
coupling reagents and additives used in peptide chemistry.19
Table 1
Conversion of thiosemicarbazide (3a) to N,5-diphenyl-2-amino-1,3,4-oxadiazole
(4a) mediated by coupling reagents
Coupling reagent
Time (h)
Yield (%)
DIC
DCC
CDI
20
24
24
12
85
50
63
85
2. Results and discussion
TBTU
We began our investigation with thiosemicarbazide 3a, which
was synthesized via reaction of benzohydrazide and phenyl-
isothiocyanate. Thiosemicarbazides were prepared in good to high
yields (75e88%) by mixing equimolar amounts of the corresponding
hydrazides and isothiocyanate derivatives in MeOH at room tem-
perature for 4 h, in some cases, the products were obtained under
solvent-free conditions. The mixture was heated at 50 ꢀC in DMF in
the presence of DIEA as base and DIC, DCC, CDI, or TBTU as coupling
reagents producing the desired 2-amino-1,3,4-oxadiazole in 85, 50,
63, 85% yields, respectively. According to these results, TBTU was
selected as the best coupling reagent for the synthesis of 1,3,4-
oxadiazoles. The results are summarized in Table 1.
DIC: N,N’-diisopropylcarbodiimide.
DCC: N,N’-dicyclohexylcarbodiimide.
CDI: N,N’-carbonyldiimidazole.
TBTU: O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium tetrafluoroborate.
Table 2
Results of cyclization of thiosemicarbazide (3a) via metal desulfurizing reagents
Desulfurizing agent
Time (h)
Yield (%)
Hg(OAc)2
Zn(OAc)2
Cu(OAc)2
p-TsCl/Pyr
12
24
24
24
75
d
Trace
50
Alternatively, other desulfurizing agents such as tosyl chloride,
mercury acetate, zinc acetate, copper acetate were examined under
the same conditions. The results are summarized in Table 2.
Using toxic materials such as Hg(OAc)2 is highly undesirable.
Meanwhile, the yield of the desired product (3a) was low compared
to TBTU as coupling reagent. According to these results, TBTU was
selected as the best reagent for the cyclization. After finding suit-
able conditions, the scope and limitations of this reaction were
explored by using different hydrazides 1aee and isothiocyanates
2aeg. The results are summarized in Table 3.
The presence of electron-donating groups on the benzhydrazide
ring showed higher activity with higher yields (Table 3, 4d and 4h)
compared to electron-withdrawing groups. The structures of the
products 4ael were deduced from their HR-ESI mass spectrometry
and NMR spectroscopic data. Meanwhile, X-ray crystallographic
analysis confirmed the structure of the product (4c) and showed
this aim, benzoyl isothiocyanate was selected as starting material,
and the desired 1,3,4-oxadiazoles were synthesized, which contain
the amide moiety (compounds 4l and 4k).
The possible mechanism for the synthesis of 2,5-disubstituted
1,3,4-oxadiazolesis shownin Scheme 2. This conversion involves the
initial reaction of the sulfur of thiosemicarbazide with the uronium
salt to form the desired intermediate (A), then the subsequent cy-
clization ofintermediate(A) followed bythe eliminationof thetetra-
methythiourea group leads to the desired product. On the basis of
the established chemistry of TBTU, it is reasonable to assume that its
activation has an essential role in the cyclization reaction. Mean-
while, the same activation could be done using carbodiimides, but in
this case, urea derivatives are generated as by-products.

S. Maghari et al. / Tetrahedron 69 (2013) 2075e2080
2077
Table 3
Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles
Hydrazide
Isothiocyanate
Product
Hydrazide
Isothiocyanate
Product
2a
1c
1a
2a
2b
4g(87%)
4a(85%)
1c
1a
2d
2a
4h(92%)
4b(87%)
4c(86%)
4d(90%)
1d
1e
1a
1a
2c
4i(70%)
4j(66%)
2a
2d
1a
1a
1a
2f
2e
4k(70%)
4e(55%)
4f(40%)
1b
2g
2a
4l(80%)
Reaction conditions: hydrazide (1 mmol), isothiocyanate derivatives (1 mmol), coupling reagent (1.5 mmol), DIEA (1 mmol).
Fig. 2. The ORTEP structure of compound 4c.

2078
S. Maghari et al. / Tetrahedron 69 (2013) 2075e2080
O
O
S
R2
NH
DIEA
R1
NHNH2
R1
SCN R2
2
N
N
+
+
N
HN NH
3
1
BF4
O
R2 = Ar, ArC
O
OH
N
N
Proton exchange
_
N
(HOBT)
S
N
BF4
N
_
R1
N
N
O
O
R1
S
NH
R2
NH
R2
N
N
HN
N
4a-l
(A)
Scheme 2. The possible mechanism for the synthesis of 4ael.
3. Conclusion
MeOH and dried. The product was further purified by re-
crystallization from MeOH.
Inconclusion, a facile and efficient approach to the synthesis of 2,5-
disubstituted 1,3,4-oxadiazoles through the cyclodesulfurization re-
action of thiosemicarbazides in the presence of TBTU as an uronium
coupling reagent has been developed. The present methodology offers
several advantages, such as simple and easy work-up procedure, mild
reaction conditions and in environmentally benign compared to other
reported methods.
4.3.1. N,5-Diphenyl-1,3,4-oxadiazol-2-amine
(201 mg, 85%); mp: 194e196 ꢀC; Rf (25% EtOAc/hexane) 0.42; nmax
(KBr): 1572, 1666, 3222 cmꢁ1
dH (500 MHz, DMSO-d6): 7.00 (t, 1H, J
3.7 Hz, HeAr), 7.35 (t, 2H, J 7.7 Hz, HeAr), 7.54e7.55 (m, 3H, HeAr),
7.61 (d, 2H, J 8.0 Hz, HeAr), 7.88e7.93 (m, 2H, HeAr), 10.62 (s, 1H,
NH); dC (125 MHz, DMSO): 117.0, 121.8, 123.8, 125.5, 129.0, 129.3,
130.9, 138.6, 157.7, 159.9; HR-mass (ESI) calcd for C28H23N6O2
[2MþH]þ 475.1877, found 475.1877.
(4a). White
solid
;
4. Experimental section
4.1. General
4.3.2. 5-Phenyl-N-p-tolyl-1,3,4-oxadiazol-2-amine (4b). White solid
(218 mg, 87%); mp: 193e196 ꢀC; Rf (25% EtOAc/hexane) 0.45; nmax
(KBr): 1617, 3257 cmꢁ1
; dH (500 MHz, DMSO-d6): 2.24 (s, 3H, eCH3),
Commercially available materials were used without further
purification. Melting points were determined on an Electrothermal
9100 apparatus and are uncorrected. IR spectra were obtained on
an ABB FT-IR FTLA 2000 spectrometer. 1H NMR and 13C NMR
spectra were run on Bruker DRX-500 AVANCE and Bruker DRX-300
AVANCE spectrometers at 500 and 300 MHz for 1H NMR, and 125
and 75 MHz for 13C NMR. DMSO was used as the solvent. High-
resolution mass spectra were recorded on Mass-ESI-POS (Apex Qe-
FT-ICR instrument) spectrometer.
7.15 (d, 2H, J 8.3 Hz, HeAr), 7.50 (d, 2H, J 8.4 Hz, HeAr), 7.54e7.56
(m, 3H, HeAr), 7.87e7.89 (m, 2H, HeAr), 10.53 (s, 1H, NH); dC
(125 MHz, DMSO-d6): 20.3, 117.1, 123.9, 125.4, 129.2, 129.4, 130.7,
130.8, 136.1, 157.6, 160.0; HR-mass (ESI) calcd for C15H14N3O
[MþH]þ 252.1133, found 252.1133.
4.3.3. 5-Phenyl-N-m-tolyl-1,3,4-oxadiazol-2-amine (4c). White solid
(215 mg, 86%); mp: 192e193 ꢀC; Rf (25% EtOAc/hexane) 0.55; nmax
(KBr): 1594, 1665, 3316 cmꢁ1
; dH (500 MHz, DMSO-d6): 2.30 (s, 3H,
eCH3), 6.82 (d, 1H, J 7.5 Hz, HeAr), 7.23 (t, 1H, J 7.8 Hz, HeAr),
7.40e7.43 (m, 2H, HeAr), 7.55e7.57 (m, 3H, HeAr), 7.87e7.93 (m, 2H,
HeAr), 10.61 (s, 1H, NH); dC (125 MHz, DMSO-d6): 21.2, 114.2, 117.5,
122.6, 123.8, 125.5, 128.9, 129.3, 130.9, 138.3, 138.5, 157.6, 159.9; HR-
mass (ESI) calcd for C15H14N3O [MþH]þ 252.1131, found 252.1130,
calcd for C15H13N3NaO [MþNa]þ 274.0949, found 274.0945, calcd for
C15H13KN3O [MþK]þ 290.0689, found 290.0689. Colourless crystal
(needle), dimensions 0.75ꢂ0.10ꢂ0.02 mm3, crystal system mono-
4.2. General procedure for the synthesis of 2-aryl-N-arylhy-
drazinecarbothioamide and N-(2-benzoylhydrazinecarbonot-
hioyl)benzamide (3ael)
Arylhydrazide (1 mmol) and arylisothiocyanate (1 mmol) were
combined in MeOH (4 mL) in a 20-mL round-bottom flask at room
temperature and stirred for 4 h. The resultant precipitate was col-
lected by filtration, washed with MeOH and dried.
ꢀ
ꢀ
clinic, space group P21/c, Z¼4, a¼13.192(6) A, b¼5.700(3) A,
3
ꢀ
ꢀ
¼90ꢀ,
b
¼93.888(11)ꢀ,
g
¼90 , V¼1292.9(11) A ,
ꢀ
c¼17.232(8) A,
a
4.3. General procedure for the synthesis of 2,5-disubstituted
1,3,4-oxadiazoles (4ael)
r
¼1.291 g/cm3, ꢀT¼200(2) K, qmax¼23.25ꢀ, radiation Mo
Ka,
ꢀ
l
¼0.71073 A, 0.3 omega-scans with CCD area detector, covering
a whole sphere in reciprocal space, 8356 reflections measured, 1856
unique (R(int)¼0.0823), 1206 observed (I>2s(I)), intensities were
correctedforLorentz and polarizationeffects, anempiricalabsorption
correctionwas applied using SADABS21a based on the Laue symmetry
Thiosemicarbazide (1 mmol), DIEA (1 mmol) and coupling re-
agent (1.5 mmol) were added to DMF (3 mL) with magnetic stirring.
The mixture was heated 50 ꢀC. When the reaction was completed as
monitored by TLC, the mixture was cooled to room temperature.
The solvent was removed in vacuo and the residue was extract with
water. The solid formed was isolated by filtration, washed with
of the reciprocal space,
m
¼0.08 mmꢁ1, Tmin¼0.94, Tmax¼1.00, struc-
turesolvedbydirectmethodsandrefinedagainstF2 withafull-matrix

S. Maghari et al. / Tetrahedron 69 (2013) 2075e2080
2079
least-squaresalgorithmusingtheSHELXTL(Version2008/4)software
239.0926, calcd for
261.0746.
C
13H10N4NaO [MþNa]þ 261.0746, found
package,21b 177 parameters refined, hydrogen atoms were treated
using appropriate riding models, except of H10, which was refined
isotropically, goodness of fit 0.97 for observed reflections, final re-
sidual values R1(F)¼0.061, wR(F2)¼0.146 for observed reflections,
4.3.10. N-Phenyl-5-(pyrazin-2-yl)-1,3,4-oxadiazole-2-amine (4j).
Brown solid (157 mg, 66%); mp: 219e220 ꢀC; Rf (25% EtOAc/hexane)
ꢀꢁ3
residual electron density ꢁ0.25 to 0.24 e A . CCDC 900992 contains
0.35; nmax (KBr): 1622, 3290 cmꢁ1
; dH (500 MHz, DMSO-d6): 7.02 (s,
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1H, HeAr), 7.36 (s, 2H, HeAr), 7.61 (s, 2H, HeAr), 8.77 (s, 2H, HeAr),
9.25 (s, 1H, HeAr), 10.93 (s, 1H, NH); dC (125 MHz, DMSO-d6): 117.2,
122.2, 129.1, 138.2, 139.3, 142.6, 144.7, 145.8, 155.8, 160.8; HR-mass
(ESI) calcd for C12H10N5O [MþH]þ 240.0879, found 240.0879, calcd
for C12H9N5NaO [MþNa]þ 262.0697, found 262.0698.
4.3.4. N-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazol-2-amine
(4d). White solid (240 mg, 90%); mp: 214e217 ꢀC; Rf (25% EtOAc/
hexane) 0.34; nmax (KBr): 1617, 3257 cmꢁ1
;
dH (500 MHz, DMSO-d6):
4.3.11. 3-Ethyl-N-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide
3.72 (s, 3H, eOCH3), 6.94 (d, 2H, J 9.1 Hz, HeAr), 7.52 (d, 2H, J 2.1 Hz,
HeAr), 7.53e7.56 (m, 3H, HeAr), 7.86e7.88 (m, 2H, HeAr), 10.45 (s,
1H, NH); dC (125 MHz, DMSO-d6): 55.2, 114.3, 118.5, 123.9, 129.3,
130.8, 131.8, 154.4, 157.4, 160.1; HR-mass (ESI) calcd for C30H27N6O4
[2MþH]þ 535.2092, found 535.2091.
(4k). White solid (179 mg, 70%); mp: 217e219 ꢀC; Rf (25% EtOAc/
hexane) 0.40; nmax (KBr): 1583, 1630, 1716 cmꢁ1
; dH (500 MHz,
DMSO-d6): 2.38 (s, 3H, HeAr), 7.41e7.46 (m, 2H, HeAr), 7.59e7.60
(m, 3H, HeAr), 7.82e7.86 (m, 2H, HeAr), 7.95e7.97 (m, 2H, HeAr),
12.12 (s, 1H, NH); dC (125 MHz, DMSO-d6): 20.8, 123.3, 125.4, 126.0,
128.4, 128.7, 129.3, 131.6, 132.3, 133.4, 137.9, 158.0, 160.9, 165.3; HR-
mass (ESI) calcd for C16H14N3O2 [MþH]þ 280.1080, found 280.1080,
calcd for C16H12N3NaO2 [MþNa]þ 302.0900, found 302.0900.
4.3.5. N-(4-Chlorophenyl)-5-phenyl-1,3,4-oxadiazol-2-amine
(4e). White solid (149 mg, 55%); mp: 229e230 ꢀC; Rf (25% EtOAc/
hexane) 0.55; nmax (KBr): 1586,1603, 3203 cmꢁ1
; dH (500 MHz, DMSO-
d6): 7.40 (d, 2H, J 8.6 Hz, HeAr), 7.55e7.56 (m, 3H, HeAr), 7.63 (d, 2H, J
8.7 Hz, HeAr), 7.88 (m, 2H, HeAr), 10.82 (s, 1-H, NH); dC (125 MHz,
DMSO-d6): 118.6, 123.7, 125.4, 125.5, 128.9, 129.3, 131.0, 137.6, 157.8,
159.6; HR-mass (ESI) calcd for C14H11N3O35Cl [MþH]þ 272.0587, found
272.0586, calcd for C14H10N3NaO35Cl [MþNa]þ 294.0406, found
294.0406.
4.3.12. 3-Methoxy-N-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide
(4l). White solid (236 mg, 80%); mp: 149e150 ꢀC; Rf (25% EtOAc/
hexane) 0.35; nmax (KBr): 1631, 1708, 3213 cmꢁ1
; dH (300 MHz,
DMSO-d6): 3.83 (s, 3H, HeOMe), 7.21e7.22 (m, 1H, HeAr),
7.47e7.61 (m, 6H, HeAr), 7.96 (br s, 2H, HeAr), 12.17 (br s, 1H, NH);
dC (125 MHz, DMSO-d6): 55.4, 113.0, 119.0, 120.0, 123.3, 126.0, 129.4,
129.8, 131.7, 133.6, 158.1, 159.2, 165.5; HR-mass (ESI) calcd for
C16H14N3O3 [Mþ1]þ 296.1032, found 296.1031, calcd for
C16H13N3NaO3 [MþNa]þ 318.0851, found 318.0852.
4.3.6. 5-(3-Chlorophenyl)-N-phenyl-1,3,4-oxadiazole-2-amine
(4f). White solid (108 mg, 40%); mp: 188e191 ꢀC; Rf (25% EtOAc/
hexane)0.45;nmax (KBr):1578,1615,3266cmꢁ1
;dH (500MHz,DMSO-
d6): 7.00 (t, 2H, J 7.3 Hz, HeAr), 7.35 (t, 2H, J 7.9 Hz, HeAr), 7.54e7.65
(m, 4H, HeAr), 7.82 (s, 1H, HeAr), 7.84 (br s, 1H, HeAr), 10.74 (s, 1H,
NH); dC (125 MHz, DMSO-d6): 116.7, 117.1, 122.0, 124.1, 125.0, 125.7,
128.9,129.1,130.6,131.3,133.9,138.4,156.5,160.1; HR-mass (ESI) calcd
for C14H11N3O35Cl [MþH]þ 272.0585, found 272.0585.
Acknowledgements
S.B. gratefully acknowledges the Alexander von Humboldt
Foundation for a research fellowship. We also thank the Ministry of
Health and Medical Education (Iran) and also the Presidential Office
Deputy of Science and Technology for financial support.
4.3.7. N-Phenyl-5-(thiophene-2-yl)-1,3,4-oxadiazol-2-amine
(4g). White solid (211 mg, 87%); mp: 187e188 ꢀC; Rf (25% EtOAc/
Supplementary data
hexane) 0.40; nmax (KBr): 1581,1673 cmꢁ1
; dH (500 MHz, DMSO-d6):
7.00 (t, 1H, J 7.4 Hz, HeAr), 7.24 (dd, 1H, J 4.9, 3.8 Hz, HeAr), 7.35 (t,
2H, J 8.4 Hz, HeAr), 7.59 (d, 2H, J 7.8 Hz, HeAr), 7.63 (dd, 1H, J 3.7,
1.1 Hz, HeAr), 7.83 (dd, 1H, J 5.0, 1.1 Hz, HeAr), 7.93 (s, 1-H, NH); dC
(125 MHz, DMSO-d6): 117.0, 121.9, 124.9, 128.2, 128.5, 129.0, 129.8,
138.5, 154.1, 159.3; HR-mass (ESI) calcd for C12H10N3OS [MþH]þ
244.0541, found 244.0541.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.11.071.
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4.3.8. N-(4-Methoxyphenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazol-2-
amine (4h). White solid (251 mg, 92%); mp: 200e203 ꢀC; Rf (25%
EtOAc/hexane) 0.35; nmax (KBr): 1586, 1683, 3290 cmꢁ1
; dH
(500 MHz, DMSO-d6): 3.71 (s, 3H, eOCH3), 6.93 (d, 2H, J 7.6 Hz,
HeAr), 7.23 (br s, 1H, thienyl), 7.49 (d, 2H, J 7.6 Hz, HeAr), 7.50 (d,
2H, J 7.6 Hz, HeAr), 7.60 (br s, 1H, H-thienyl), 7.81 (br s, 1H, thienyl),
10.46 (br s, 1H, NH); dC (125 MHz, DMSO-d6): 55.2, 114.3, 118.6,
125.1, 128.1, 128.4, 129.6, 131.8, 153.9, 154.5, 159.6; HR-mass (ESI)
calcd for C13H12N3O2S [MþH]þ 274.0643, found 274.0643, calcd for
C13H11N3NaO2S [MþNa]þ 296.0462, found 296.0462.
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4.3.9. N-Phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amine (4i). White
solid (166 mg, 70%); mp: 214e217 ꢀC; Rf (25% EtOAc/hexane) 0.45;
nmax (KBr): 1565, 1615, 3267 cmꢁ1
; dH (500 MHz, DMSO-d6): 7.02 (br
s, 1H, HeAr), 7.36 (br s, 2H, HeAr), 7.61 (d, 2H, J 6.9 Hz, HeAr), 7.78
(br s, 2H, HeAr), 8.76 (br s, 2H, HeAr),10.85 (s,1H, NH); dC (125 MHz,
DMSO-d6): 117.2, 119.1, 122.2, 129.1, 130.7, 138.3, 150.8, 156.2, 160.5;
HR-mass (ESI) calcd for C13H11N4O [MþH]þ 239.0926, found

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