Efficient synthesis of 1,3,4-oxadiazoles conjugated to thiophene or furan rings via an ethenyl linker

Article abstract of DOI:10.1055/s-0033-1338454

A novel and efficient synthesis of 5-substituted 2-[2-(2-furyl)ethenyl]-1, 3,4-oxadiazoles and 2-[2-(2-thienyl)ethenyl]-1,3,4-oxadiazoles by cyclocondensation of the appropriate 3-(2-furyl)- and 3-(2-thienyl) acrylohydrazides with triethyl orthoesters in the presence of glacial acetic acid is reported. The formation of symmetrically substituted 2,5-bis[2-(2-furyl)ethenyl]-1,3,4-oxadiazole and 2,5-bis[2-(2-thienyl)ethenyl]- 1,3,4-oxadiazole from the corresponding N,N′-diacylhydrazines under the influence of phosphorus oxychloride is also described. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338454

1950▌
PAPER
paper
Efficient Synthesis of 1,3,4-Oxadiazoles Conjugated to Thiophene or Furan
Rings via an Ethenyl Linker
Conjugated 1,3,4-Oxadiazole Derivatives
Agnieszka Kudelko,* Karolina Jasiak
Department of Chemical Organic Technology and Petrochemistry, The Silesian University of Technology, Krzywoustego 4, 44100 Gliwice,
Poland
Fax +48(32)2371021; E-mail: Agnieszka.Kudelko@polsl.pl
Received: 11.03.2013; Accepted after revision: 08.04.2013
cides, fungicides or insecticides.7d,e Conjugated macrocy-
Abstract: A novel and efficient synthesis of 5-substituted 2-[2-(2-
clic arrangements based on the 1,3,4-oxadiazole fragment
furyl)ethenyl]-1,3,4-oxadiazoles and 2-[2-(2-thienyl)ethenyl]-
exhibit interesting electron-transfer or luminescent prop-
erties and are used in OLEDs, scintillators and photosen-
1,3,4-oxadiazoles by cyclocondensation of the appropriate 3-(2-fu-
ryl)- and 3-(2-thienyl)acrylohydrazides with triethyl orthoesters in
the presence of glacial acetic acid is reported. The formation of sitive materials. They are also applied in the production of
symmetrically substituted 2,5-bis[2-(2-furyl)ethenyl]-1,3,4-oxadia-
zole and 2,5-bis[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole from the
corresponding N,N′-diacylhydrazines under the influence of phos-
heat-resistant polymers, blowing agents, laser dyes and
optical brighteners.4
The most popular methods to synthesise 1,3,4-oxadia-
zoles involve the use of acid hydrazides as cycloconden-
sation substrates with carboxylic acids,8 aromatic
aldehydes7c and orthoesters.9 The reactions of
diacylhydrazines10 with a range of cyclodehydrating
agents, heterocyclization of semicarbazide, thiosemicar-
bazide and selenosemicarbazide derivatives,11 or transfor-
mations involving another ring, such as 1,2,4-
oxadiazole12a or tetrazole,12b,c may also be employed.
phorus oxychloride is also described.
Key words: cyclization, heterocycles, furans, thiophenes, 1,3,4-
oxadiazoles
During the past 20 years, there has been a significant in-
crease of interest in organic compounds exhibiting lumi-
nescent properties.1 An optimised organic luminophore is
usually an extended π-conjugated chromophore system
showing the proper electron- and hole-transporting prop-
erties, a high external quantum efficiency, and both ther-
mal and chemical stability.2 A literature survey reveals
examples of the modification of luminophore electron-
transporting properties by direct or indirect conjugation
with other electron-deficient systems such as pyridines,
furans, thiophenes, selenophenes or tellurophenes.3 It has
been proven that the ability of these arrangements to elec-
tropolymerise to linear PPV-type conducting systems and
the resulting strong electroluminescence qualifies them as
materials with potential applications in polymer and ma-
terial science. Amongst the aromatic compounds used
widely in the production of new materials for optoelec-
tronics, particularly in organic light-emitting diodes
(OLEDs), derivatives of 1,3,4-oxadiazole substituted with
heteroaryl groups at the 2- and 5-positions play an impor-
tant role.3a,4
The aim of this work was to study the synthesis of new,
extended heterocyclic 1,3,4-oxadiazole scaffold based ar-
rangements that are conjugated through an ethenyl linker
to other heteroaromatic fragments such as thiophene or fu-
ran. These fragment hybrids are promising monomers for
optoelectronic applications because they combine differ-
ent electron-deficient rings featuring excellent electron-
transporting properties with high luminous efficiencies.
To the best of our knowledge, the synthesis of 1,3,4-oxa-
diazoles that are derived from α,β-unsaturated acid hydra-
zides and triethyl orthoesters, and are conjugated via an
ethenyl linker to thiophene or furan rings, has not been
previously reported. This approach seemed to be quite
promising due to the fact that, contrary to other synthons
used in the formation of 1,3,4-oxadiazoles, orthoesters
possess three easy-leaving alkoxy groups, which ensures
the cyclization occurs readily and under relatively mild
conditions.
1,3,4-Oxadiazoles belong to the group of five-membered,
non-naturally occurring heterocycles. These compounds
were first mentioned in the literature during the late 1950s
as the products of the reaction between aryl carboxylic
acid hydrazides and orthoesters.5 1,3,4-Oxadiazoles are
well known for their biological interactions.6 Many 1,3,4-
oxadiazoles are used to fight infections involving AIDS
and exhibit antibacterial, anticonvulsant and anticancer
activities.7a–c They are also applied in agriculture as herbi-
Hydrazides of α,β-unsaturated acids were used as precur-
sors to the 1,3,4-oxadiazole hybrids. The starting hydra-
zides, 3-(2-furyl)acrylohydrazide (5a) and 3-(2-
thienyl)acrylohydrazide (5b), were prepared from the ap-
propriate commercially available heteroaromatic alde-
hydes according to a short synthetic procedure (Scheme
1).
Thus, the starting aldehydes, 2-furancarboxaldehyde (1a)
and 2-thiophenecarboxaldehyde (1b), were each treated
with malonic acid in pyridine in the presence of catalytic
amounts of piperidine. Knoevenagel condensation and
successive decarboxylation of the intermediate dicarbox-
SYNTHESIS 2013, 45, 1950–1954
Advanced online publication: 08.05.2013
DOI: 10.1055/s-0033-1338454; Art ID: SS-2013-T0197-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

PAPER
Conjugated 1,3,4-Oxadiazole Derivatives
1951
O
O
CHO 1) CH2(COOH)2,
piperidine, Δ
OH
OK
2) HCl
KOH
X
X
X
– CO2
1a,b
X = O, S
2a,b
3a,b
O
ClCOOEt
NHNH2
O
O
X
5a,b
N2H4•H2O
O
OEt
O
H
N
X
X
4a,b
N
H
X
O
X
Yield (%)
X
Yield (%)
6a,b
2a
3a
5a
6a
O
O
O
O
90
95
89
10
2b
S
S
S
S
69
98
85
12
3b
5b
6b
Scheme 1
ylic acids resulted in the formation of the α,β-unsaturated The resulting acid hydrazides 5a,b were subjected to heat-
monocarboxylic acids, 3-(2-furyl)acrylic acid (2a) and 3- ing with an excess of the triethyl orthoesters (orthoacetate,
(2-thienyl)acrylic acid (2b), in high yields. They were orthopropionate or orthobenzoate; R = Me, Et, Ph) in gla-
transformed into the hydrazides 5a,b, via the mixed anhy- cial acetic acid, yielding the 2-[2-(2-furyl)ethenyl]-1,3,4-
drides 4a,b, produced in a one-pot, two-step procedure.
oxadiazoles 7a–c and the 2-[2-(2-thienyl)ethenyl]-1,3,4-
oxadiazoles 7d–f substituted at the 5-position with a phe-
nyl or an alkyl group (Table 2). The highest yields were
obtained in the reactions with triethyl orthobenzoate,
where extended and stable conjugated arrangements were
formed (7c: 84%, 7f: 89%). In contrast to the previously
examined 2-styryl-1,3,4-oxadiazoles, prepared in the
reaction of cinnamic acid hydrazide and triethyl ortho-
esters,9c the α,β-unsaturated acid hydrazides conjugated
with a furan or thiophene ring were much more reactive
than their phenyl-containing counterpart. The reactions
between hydrazides 5a,b and the alkyl-group-bearing or-
thoesters (R = Me, Et) were complete after 3–4 hours at
First, the potassium salt 3a,b of the corresponding acid
was treated with ethyl chloroformate, and then hydrazine
hydrate was added to obtain the desired product 5a,b;
however, the main reaction was accompanied by the for-
mation of significant quantities of high-melting N,N′-di-
acylhydrazines 6a,b. These products arose from the
bidentate nucleophile hydrazine hydrate mediated substi-
tution of the anhydrides 4a,b. An increase of the molar ra-
tio between the hydrazine hydrate and salt/ethyl
chloroformate system resulted in high yields of the de-
sired hydrazide 5a (Table 1, entry 2). Unfortunately, the
number of solvents applicable here was rather limited be-
cause the intermediate anhydride 4 is a relatively reactive
compound. However, it should also be noted that the for-
mation of hydrazide 5a proceeded more effectively in a
polar solvent such as acetonitrile (Table 1, entry 4). Thus,
the synthesis of the second key starting material, 3-(2-
thienyl)acrylohydrazide (5b), was successfully conducted
with excess hydrazine hydrate in acetonitrile solution.
Table 2 Reaction of 3-(2-Furyl)acrylohydrazide (5a) or 3-(2-Thie-
nyl)acrylohydrazide (5b) with Triethyl Orthoesters
O
R
O
RC(OEt)3
AcOH, Δ
X
NHNH2
N
N
X
5a,b
7a–f
X = O, S
R = Me, Et, Ph
Table 1 Optimisation of the Reaction Conditions for the Preparation
of 3-(2-Furyl)acrylohydrazide (5a)
X
R
Temp
(°C)
Time
(h)
Product Yielda
(%)
Mp (°C)
Entry
Molar ratio
Solvent
Yielda (%)
3a/ClCO2Et/N2H4·H2O
of 5a
O
O
O
S
Me
Et
120
125
150
120
125
150
4.0
3.0
1.5
3.5
3.0
1.5
7a
7b
7c
7d
7e
7f
68
76
84
72
83
89
110–112
90–92
1
2
3
4
1:1:1
1:1:2
1:1:2
1:1:2
CH2Cl2
CH2Cl2
THF
35
58
86
89
Ph
Me
Et
117–119
101–103
61–63
MeCN
S
a Yield with respect to the starting 3-(2-furyl)acrylic acid (2a).
S
Ph
108–110
a Yield with respect to the starting hydrazide 5a,b.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1950–1954

1952
A. Kudelko, K. Jasiak
PAPER
Table 3 Preparation of 2,5-Bis-[2-(2-furyl)ethenyl]-1,3,4-oxadiazole (8a) and 2,5-Bis[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole (8b) from the
Corresponding N,N′-Diacylhydrazines 6a,b
X
O
H
N
X
O
POCl3, toluene, Δ
X
N
H
N
N
X
X = O, S
X
O
6a,b
8a,b
Temp (°C)
Time (h)
Product
Yielda (%)
Mp (°C)
O
S
110
110
1
1
8a
8b
72
89
179–181
173–176
a Yield with respect to the starting N,N′-diacylhydrazine 6a,b.
TLC plates using benzene–EtOAc (1:3 v/v) or MeOH–CHCl3 (1:4
v/v) as the mobile phase. FT-IR spectra were recorded between
4000 and 650 cm–1 on a Nicolet 6700 FT-IR apparatus with a Smart
iTR accessory. Mass spectra were obtained on a GC/MS Agilent
Technologies 7890A/5975C System with a Triple Axis Detector us-
ing the EI technique (70 eV).
reflux, while cinnamic acid hydrazide required up to 40
hours of conventional heating in glacial acetic acid to re-
act.9c
As already noted, reaction of the potassium salts 3a,b of
the α,β-unsaturated acids with ethyl chloroformate and
hydrazine hydrate resulted not only in the desired prod-
ucts 5a,b but also in the formation of side products, name-
ly the corresponding N,N′-diacylhydrazines 6a,b (Scheme
1). This particular group of compounds, usually prepared
from acid chlorides or acid anhydrides and hydrazides or
simply hydrazine hydrate, is widely exploited in the syn-
thesis of 1,3,4-oxadiazoles. The reactions are conducted
under the influence of typical dehydrating agents such as
polyphosphoric acid, phosphorus oxychloride, thionyl
chloride and boron trifluoride–diethyl ether complex.11
The great advantage of the methods making use of phos-
phorus oxychloride or thionyl chloride and proceeding in
non-polar solvents is the ease of the post-reaction workup.
Thus, N,N′-diacylhydrazines 6a,b, obtained from the cor-
responding α,β-unsaturated acids 2a,b, were heated at re-
flux with phosphorus oxychloride in toluene for a short
time to obtain other conjugated aromatic products, the
symmetrically substituted 2,5-bis[2-(2-heteroaryl)ethe-
nyl]-1,3,4-oxadiazoles 8a,b, in high yields (72–89%; Ta-
ble 3).
3-(2-Heteroaryl)acrylic Acids 2a,b; General Procedure
A mixture of an aldehyde 1a,b (0.38 mol), malonic acid (93.6 g,
0.90 mol), pyridine (180 mL) and piperidine (3 mL) was heated in
a steam bath, stirred for 2 h and boiled for 5 min. After cooling, the
reaction mixture was poured into cold H2O (80 mL) and treated with
concd HCl (120 mL). The precipitate was collected by filtration,
washed with H2O and dried. The crude product was crystallised
(EtOH) to yield the corresponding pure 3-(2-heteroaryl)acrylic acid
2a,b.
3-(2-Furyl)acrylic Acid (2a)
Beige solid; yield: 47.2 g (90%); mp 138–141 °C (Lit.13 139–
140 °C); Rf = 0.67 (benzene–EtOAc–AcOH, 6:2:1).
3-(2-Thienyl)acrylic Acid (2b)
White solid; yield: 40.4 g (69%); mp 147–149 °C (Lit.14 148–
149 °C); Rf = 0.53 (benzene–EtOAc–AcOH, 6:2:1).
3-(2-Heteroaryl)acrylohydrazides 5a,b and N,N′-Diacylhydra-
zines 6a,b; General Procedure
The 3-(2-heteroaryl)acrylic acid 2a,b (0.10 mol) was slowly added
to a stirred soln of KOH (5.6 g, 0.10 mol) in H2O (100 mL). The
mixture was stirred for approximately 10 min and then concentrated
using a rotary evaporator. The precipitate was washed with Et2O
(2 × 50 mL), collected by filtration and air-dried to give the corre-
sponding crude potassium salt as a white solid; yield of 3a: 16.7 g
(95%); yield of 3b: 18.8 g (98%).
In conclusion, we have demonstrated an easy and efficient
synthesis of both unsymmetrical and symmetrical 1,3,4-
oxadiazole–furan and 1,3,4-oxadiazole–thiophene hy-
brids, compounds with potential useful applications in op-
toelectronics. The methods presented here have the
advantage of providing the desired products rapidly and in
high yields, which makes them useful additions to the ex-
isting synthetic protocols.
To a stirred suspension of the potassium salt 3a,b (0.09 mol) in
MeCN (300 mL) were added ethyl chloroformate (9.8 g, 0.09 mol)
and a 1% soln of pyridine in MeCN (30 mL). The reaction mixture
was heated under reflux for 2 h and then slowly poured into a
stirred, ice-cooled suspension of hydrazine hydrate (9.0 g, 0.18 mol)
in MeCN (100 mL). After filtration, the filtrate was kept in an ice-
box overnight. After cooling, the light-yellow precipitate was col-
lected by filtration, washed with Et2O (2 × 50 mL) and air-dried,
yielding the corresponding pure N,N′-diacylhydrazines 6a,b. The
filtrate was washed with sat. aq Na2CO3 soln (2 × 50 mL), dried
over MgSO4 and concentrated using a rotatory evaporator. The
crude product was purified by silica gel column chromatography
(benzene–EtOAc, 1:3) to give the 3-(2-heteroaryl)acrylohydrazides
5a,b.
All solvents and reagents were purchased from commercial sources
and were used without additional purification. Melting points were
measured using a Stuart SMP3 melting point apparatus and are un-
corrected. Elemental analyses were performed with a Vario EL
analyser. UV spectra were recorded on a Jasco V-650 spectropho-
tometer. 1H and 13C NMR spectra were recorded in DMSO-d6 and
CDCl3 solutions using TMS as the internal standard on a Varian
Inova 300, a Varian 600 or an Agilent 400-MR spectrometer. Thin-
layer chromatography was performed on Merck silica gel 60 F254
3-(2-Furyl)acrylohydrazide (5a)
Yellow solid; yield: 12.2 g (89%); mp 108–109 °C (Lit.15 108–
110 °C); Rf = 0.18 (benzene–EtOAc, 1:3).
Synthesis 2013, 45, 1950–1954
© Georg Thieme Verlag Stuttgart · New York

PAPER
Conjugated 1,3,4-Oxadiazole Derivatives
1953
3-(2-Thienyl)acrylohydrazide (5b)
Yellow solid; yield: 12.9 g (85%); mp 105–107 °C; Rf = 0.11 (ben-
zene–EtOAc, 1:3).
2-[2-(2-Furyl)ethenyl]-5-methyl-1,3,4-oxadiazole (7a)
White solid; yield: 1.2 g (68%); mp 110–112 °C (Lit.16 114–
115 °C); Rf = 0.55 (benzene–EtOAc, 1:3).
IR (ATR): 3259, 3170, 2162, 1980, 1683, 1656, 1515, 1494, 1421,
1358, 1320, 1278, 1263, 1222, 1196, 1128, 1085, 1041, 938, 870,
829, 787, 746, 692 cm–1.
2-Ethyl-5-[2-(2-furyl)ethenyl]-1,3,4-oxadiazole (7b)
White solid; yield: 1.4 g (76%); mp 90–92 °C; Rf = 0.50 (benzene–
EtOAc, 1:3).
1H NMR (300 MHz, DMSO-d6): δ = 4.55 (br s, 2 H, NH2), 6.29 (d,
J = 15.3 Hz, 1 H, α-CH=), 7.08 (dd, J1 = 3.6 Hz, J2 = 5.1 Hz, 1 H,
C4′-H), 7.35 (d, J = 3.6 Hz, 1 H, C3′-H), 7.57 (d, J = 5.1 Hz, 1 H,
C5′-H), 7.60 (d, J = 15.3 Hz, 1 H, β-CH=), 9.31 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): δ = 119.0, 127.7, 128.3, 130.4,
131.2, 139.9, 164.2.
IR (ATR): 3133, 3113, 3070, 2985, 2941, 2162, 1980, 1788, 1730,
1650, 1632, 1586, 1521, 1471, 1443, 1391, 1375, 1317, 1292, 1259,
1191, 1153, 1082, 1066, 1029, 972, 927, 847, 820, 727, 665 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.41 (t, J = 7.5 Hz, 3 H, CH3),
2.90 (q, J = 7.5 Hz, 2 H, CH2), 6.48 (dd, J1 = 1.8 Hz, J2 = 3.3 Hz, 1
H, C4′-H), 6.57 (d, J = 3.3 Hz, 1 H, C5′-H), 6.89 (d, J = 16.2 Hz, 1
H, α-CH=), 7.26 (d, J = 16.2 Hz, 1 H, β-CH=), 7.50 (d, J = 1.8 Hz,
1 H, C3′-H).
MS (EI, 70 eV): m/z (%) = 40.1 (22), 43.9 (49), 63.0 (15), 64.9 (22),
108.0 (29), 108.9 (60), 135.0 (46), 137.0 (100), 152.9 (37), 168.0
(15) [M+].
13C NMR (75 MHz, CDCl3): δ = 10.7, 19.1, 108.0, 112.2, 113.2,
125.1, 144.3, 151.0, 164.3, 167.1.
UV (MeOH): λmax (ε) = 203.5 (10660), 306.5 nm (19120).
MS (EI, 70 eV): m/z (%) = 57.0 (23), 65.0 (20), 78.0 (15), 79.0 (20),
Anal. Calcd for C7H8N2OS: C, 49.98; H, 4.78; N, 16.65. Found: C,
49.93; H, 4.84; N, 16.67.
121.0 (35), 149.0 (31), 189.0 (100), 190.1 (51) [M+].
UV (MeOH): λmax (ε) = 220.0 (4540), 314.0 nm (36410).
N,N′-Bis[3-(2-furyl)-2-propenoyl]hydrazine (6a)
Light-yellow solid; yield: 2.4 g (10%); mp >350 °C; Rf = 0.65
(MeOH–CHCl3, 1:4).
Anal. Calcd for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C,
63.22; H, 5.29; N, 14.77.
IR (ATR): 3181, 3019, 2597, 2162, 2039, 1980, 1647, 1583, 1563,
1471, 1420, 1389, 1324, 1279, 1261, 1221, 1152, 1122, 1096, 1019,
986, 969, 928, 882, 839, 755, 694 cm–1.
2-[2-(2-Furyl)ethenyl]-5-phenyl-1,3,4-oxadiazole (7c)
White solid; yield: 2.0 g (84%); mp 117–119 °C (Lit.17 118–
119 °C); Rf = 0.74 (benzene–EtOAc, 1:3).
1H NMR (300 MHz, DMSO-d6): δ = 6.51 (d, J = 15.6 Hz, 1 H, α-
CH=), 6.60 (dd, J1 = 1.8 Hz, J2 = 3.3 Hz, 1 H, C4′-H), 6.83 (d,
J = 3.3 Hz, 1 H, C5′-H), 7.34 (d, J = 15.6 Hz, 1 H, β-CH=), 7.81 (d,
J = 1.8 Hz, 1 H, C3′-H), 10.46 (s, 1 H, NH).
2-Methyl-5-[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole (7d)
White solid; yield: 1.4 g (72%); mp 101–103 °C; Rf = 0.46 (ben-
zene–EtOAc, 1:3).
IR (ATR): 3096, 3044, 2162, 2037, 1827, 1637, 1543, 1531, 1505,
1421, 1411, 1359, 1324, 1247, 1234, 1219, 1199, 1174, 1131, 1085,
1044, 970, 857, 826, 747, 732, 669, 653 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.56 (s, 3 H, CH3), 6.79 (d,
J = 16.2 Hz, 1 H, α-CH=), 7.06 (dd, J1 = 3.6 Hz, J2 = 5.1 Hz, 1 H,
C4′-H), 7.23 (d, J = 3.6 Hz, 1 H, C3′-H), 7.37 (d, J = 5.1 Hz, 1 H,
C5′-H), 7.60 (d, J = 16.2 Hz, 1 H, β-CH=).
13C NMR (75 MHz, DMSO-d6): δ = 112.5, 114.5, 116.4, 127.3,
145.1, 150.8, 163.0.
UV (MeOH): λmax (ε) = 310.5 nm (74640).
Anal. Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C,
61.78; H, 4.63; N, 10.27.
N,N′-Bis[3-(2-thienyl)-2-propenoyl]hydrazine (6b)
Light-yellow solid; yield: 3.3 g (12%); mp 290–295 °C; Rf = 0.70
(MeOH–CHCl3, 1:4).
13C NMR (75 MHz, CDCl3): δ = 10.9, 108.8, 127.6, 128.0, 129.5,
131.0, 139.9, 162.9, 164.1.
MS (EI, 70 eV): m/z (%) = 121.0 (17), 137.0 (17), 191.0 (100),
IR (ATR): 3133, 2814, 2590, 1662, 1634, 1597, 1524, 1468, 1413,
1393, 1309, 1269, 1228, 1207, 1182, 1074, 1043, 967, 944, 929,
882, 828, 755, 719, 663 cm–1.
192.0 (22) [M+].
UV (MeOH): λmax (ε) = 203.5 (9449), 315.0 nm (24781).
1H NMR (300 MHz, DMSO-d6): δ = 6.49 (d, J = 15.3 Hz, 1 H, α-
CH=), 7.12 (dd, J1 = 3.6 Hz, J2 = 5.1 Hz, 1 H, C4′-H), 7.43 (d,
J = 3.6 Hz, 1 H, C3′-H), 7.64 (d, J = 5.1 Hz, 1 H, C5′-H), 7.69 (d,
J = 15.3 Hz, 1 H, β-CH=), 10.42 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): δ = 117.9, 128.1, 128.4, 131.1,
133.1, 139.6, 162.8.
Anal. Calcd for C9H8N2OS: C, 56.23; H, 4.19; N, 14.57. Found: C,
56.24; H, 4.23; N, 14.51.
2-Ethyl-5-[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole (7e)
White solid; yield: 1.7 g (83%); mp 61–63 °C; Rf = 0.50 (benzene–
EtOAc, 1:3).
IR (ATR): 3103, 3089, 2986, 2940, 2163, 1980, 1844, 1637, 1545,
1507, 1498, 1462, 1443, 1412, 1375, 1354, 1317, 1293, 1265, 1245,
1187, 1081, 1040, 1024, 968, 861, 848, 797, 691 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.41 (t, J = 7.5 Hz, 3 H, CH3),
2.90 (q, J = 7.5 Hz, 2 H, CH2), 6.80 (d, J = 16.2 Hz, 1 H, α-CH=),
7.05 (dd, J1 = 3.9 Hz, J2 = 4.8 Hz, 1 H, C4′-H), 7.23 (d, J = 3.9 Hz,
1 H, C3′-H), 7.36 (d, J = 4.8 Hz, 1 H, C5′-H), 7.60 (d, J = 16.2 Hz,
1 H, β-CH=).
UV (MeOH): λmax (ε) = 204.5 (17232), 319.0 nm (43457).
Anal. Calcd for C14H12N2O2S2: C, 55.24; H, 3.97; N, 9.20. Found:
C, 55.28; H, 3.90; N, 9.15.
5-Substituted 2-[2-(2-Heteroaryl)ethenyl]-1,3,4-oxadiazoles 7a–
f; General Procedure
The starting hydrazide 5a,b (10.0 mmol) was added to a mixture of
the triethyl orthoester (15.0 mmol) and glacial AcOH (10 mL). The
mixture was kept under reflux until the starting hydrazide was fully
consumed (monitored by TLC, 1–4 h). After cooling, the excess
orthoester and AcOH were evaporated under reduced pressure. The
crude product 7a–f was subjected to silica gel column chromatogra-
phy (benzene–EtOAc, 1:3) or was crystallised (benzene–hexane
mixtures).
13C NMR (75 MHz, CDCl3): δ = 10.6, 19.0, 108.9, 127.6, 128.0,
129.4, 131.0, 139.9, 163.9, 167.0.
MS (EI, 70 eV): m/z (%) = 121.0 (15), 137.0 (15), 205.0 (100),
206.0 (23) [M+].
UV (MeOH): λmax (ε) = 222.0 (5347), 320.5 nm (26702).
Anal. Calcd for C10H10N2OS: C, 58.23; H, 4.89; N, 13.58. Found:
C, 58.27; H, 4.82; N, 13.61.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1950–1954

1954
A. Kudelko, K. Jasiak
PAPER
(2) (a) Schulz, B.; Bruma, M.; Brehmer, L. Adv. Mater.
2-Phenyl-5-[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole (7f)
White solid; yield: 2.3 g (89%); mp 108–110 °C; Rf = 0.61 (ben-
zene–EtOAc, 1:3).
(Weinheim, Ger.) 1997, 9, 601. (b) Thelakkat, M.; Schmidt,
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Petty, M. C. J. Mater. Chem. 2002, 12, 173. (b) Waskiewicz,
K.; Gabański, R.; Żak, J.; Suwiński, J. Electrochem. Solid-
State Lett. 2005, 8, E24. (c) Fuks-Janczarek, I.; Reshak, A.
H.; Kuźnik, N.; Kityk, I. V.; Gabański, R.; Łapkowski, M.;
Motyka, R.; Suwiński, J. Spectrochim. Acta, Part A 2009,
72, 394. (d) Łapkowski, M.; Motyka, R.; Suwiński, J.; Data,
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Lai, Y. H.; Huang, W. Macromolecules 1999, 32, 4351.
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1077. (d) Sinigersky, V.; Wegner, G.; Schopov, I. Eur.
Polym. J. 1993, 29, 617.
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(6) Suwiński, J.; Szczepankiewicz, W. Comprehensive
Heterocyclic Chemistry III; Vol. 5; Katritzky, A. R.;
Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds.;
Chap. 6; Elsevier Science Ltd: Oxford, 2008, 398.
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Kebriaeezadeh, A. Bioorg. Med. Chem. Lett. 2004, 14, 6057.
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Tetrahedron Lett. 2006, 47, 4827. (d) Zheng, X.; Li, Z.;
Wang, Y.; Chen, W.; Huang, Q.; Liu, C.; Song, G. J.
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Zhang, Z. X. J. Agric. Food Chem. 2002, 50, 3757.
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IR (ATR): 3062, 2162, 1980, 1636, 1609, 1563, 1548, 1482, 1449,
1418, 1293, 1274, 1253, 1127, 1090, 1071, 1018, 972, 959, 924,
857, 847, 824, 744, 728, 687 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.89 (d, J = 16.2 Hz, 1 H, α-CH=),
7.08 (dd, J1 = 3.6 Hz, J2 = 5.1 Hz, 1 H, C4′-H), 7.27 (d, J = 3.6 Hz,
1 H, C3′-H), 7.39 (d, J = 5.1 Hz, 1 H, C5′-H), 7.49–7.56 (m, 3 H,
C3′′-H, C4′′-H, C5′′-H), 7.74 (d, J = 16.2 Hz, 1 H, β-CH=), 8.09–
8.12 (m, 2 H, C2′′-H, C6′′-H).
13C NMR (75 MHz, CDCl3): δ = 108.9, 123.9, 126.9, 127.9, 128.2,
129.0, 129.7, 131.5, 131.7, 140.1, 163.9, 164.0.
MS (EI, 70 eV): m/z (%) = 77.0 (15), 97.0 (100), 110.0 (23), 254.0
(51) [M+].
UV (MeOH): λmax (ε) = 203.0 (20020), 262.5 (12770), 336.0 nm
(30570).
Anal. Calcd for C14H10N2OS: C, 66.12; H, 3.96; N, 11.02. Found:
C, 66.08; H, 3.90; N, 11.07.
2,5-Bis[2-(2-heteroaryl)ethenyl]-1,3,4-oxadiazoles 8a,b; Gener-
al Procedure
A soln of the N,N′-diacylhydrazine 6a,b (3.7 mmol) and POCl3 (10
mL) in anhyd toluene (20 mL) was heated under reflux for approx-
imately 1 h. After cooling, the precipitate was collected by filtra-
tion, air-dried and crystallised (i-PrOH) to give the corresponding
pure 2,5-bis[2-(2-heteroaryl)ethenyl]-1,3,4-oxadiazole 8a,b.
2,5-Bis[2-(2-furyl)ethenyl]-1,3,4-oxadiazole (8a)
Brown solid; yield: 0.7 g (72%); mp 179–181 °C (Lit.17 126–
127 °C); Rf = 0.43 (benzene–EtOAc, 1:3).
2,5-Bis[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole (8b)
Beige solid; yield: 0.9 g (89%); mp 173–176 °C; Rf = 0.67 (ben-
zene–EtOAc, 1:3).
(9) (a) Kudelko, A.; Zieliński, W.; Ejsmont, K. Tetrahedron
2011, 67, 7838. (b) Kudelko, A. Tetrahedron 2012, 68,
3616. (c) Kudelko, A.; Zieliński, W. Tetrahedron Lett. 2012,
53, 76.
IR (ATR): 3085, 2163, 2035, 1632, 1562, 1541, 1493, 1416, 1356,
1264, 1216, 1193, 1127, 1040, 989, 947, 854, 826, 707 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 6.96 (d, J = 16.2 Hz, 1 H, α-
CH=), 7.17 (dd, J1 = 3.6 Hz, J2 = 5.1 Hz, 1 H, C4′-H), 7.56 (d,
J = 3.6 Hz, 1 H, C3′-H), 7.72 (d, J = 5.1 Hz, 1 H, C5′-H), 7.84 (d,
J = 16.2 Hz, 1 H, β-CH=).
13C NMR (75 MHz, DMSO-d6): δ = 108.2, 128.6, 129.3, 130.4,
131.7, 139.5, 162.9.
(10) (a) Tully, W. R.; Cardner, C. R.; Gillespie, R. J.; Westwood,
R. J. Med. Chem. 1991, 34, 2060. (b) Cao, S.; Qian, X.;
Song, G.; Huang, Q. J. Fluorine Chem. 2002, 117, 63. (c) El
Kain, L.; Le Menestrel, I.; Morgentin, R. Tetrahedron Lett.
1998, 39, 6885. (d) Tandon, V. K.; Chhor, R. B. Synth.
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Loong, Y.; Oakley, P. J. Tetrahedron Lett. 1999, 40, 3275.
(11) (a) Shaker, R. M.; Mahmoud, A. F.; Abdel-Latif, F. F.
Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 397.
(b) Zarghi, A.; Hajimahdi, Z.; Mohebbi, S.; Rashidi, H.;
Mozaffari, S.; Sarraf, S.; Faizi, M.; Tabatabaee, S. A.;
Shafiee, A. Chem. Pharm. Bull. 2008, 56, 509. (c) Xie, Y.;
Liu, J.; Yang, P.; Shi, X.; Li, J. Tetrahedron 2011, 67, 5369.
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Chem. 2002, 67, 6253. (b) Dupau, P.; Epple, R.; Thomas, A.
A.; Fokin, V. V.; Sharpless, K. B. Adv. Synth. Catal. 2002,
344, 421. (c) Huisgen, R.; Sauer, J.; Sturm, H. J.; Markgraf,
J. H. Chem. Ber. 1960, 93, 2106.
MS (EI, 70 eV): m/z (%) = 65.0 (15), 109.0 (32), 137.0 (49), 285.0
(100), 286.0 (38) [M+].
UV (MeOH): λmax (ε) = 230.6 (8320), 309.4 (19850), 356.6 nm
(28370).
Anal. Calcd for C14H10N2OS2: C, 58.72; H, 3.52; N, 9.78. Found: C,
58.66; H, 3.59; N, 9.74.
Acknowledgment
The authors thank Professor Wojciech Zieliński for stimulating
discussions and Anna Kuźnik, Ph.D., from The Silesian University
of Technology, for FT-IR analyses.
(13) Karminski-Zamola, G.; Jakopcic, K. Croat. Chem. Acta
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Synthesis 2013, 45, 1950–1954
© Georg Thieme Verlag Stuttgart · New York