An Improved Synthesis of 2-Aryl- and 2-Alkenyl-1,3,4-oxadiazoles by Using Copper(II) Oxide Nanoparticles as a Catalyst 1

Article abstract of DOI:10.1055/s-0034-1380923

2-Aryl- and 2-alkenyl-1,3,4-oxadiazoles were efficiently synthesized in high yields by treatment of 1,3,4-oxadiazoles with aryl or alkenyl halides, respectively, in the presence of copper(II) oxide nanoparticles as a catalyst. The reusability of the catalyst is an important advantage in relation to practical applications of this synthesis.

Full text of DOI:10.1055/s-0034-1380923

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2831–2838
paper
2831
N. Salva Reddy et al.
Paper
Synthesis
An Improved Synthesis of 2-Aryl- and 2-Alkenyl-1,3,4-oxadiazoles
by Using Copper(II) Oxide Nanoparticles as a Catalyst1
nano CuO (10 mol%)
Ph3P (30 mol%)
K2CO3 (2 equiv)
N. Salva Reddy
P. Raghavendar Reddy
Biswanath Das*
N
N
Ar2
Ar2X
diglyme, reflux
10–24 h
Ar1
O
N
N
8 examples
70–85%
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India
biswanathdas@yahoo.com
Ar1
O
nano CuO (10 mol%)
Ph3P (30 mol%)
K2CO3 (2 equiv)
Ar2
N
N
Ar1
O
X
Ar2
diglyme, reflux
18–24 h
10 examples
71–81%
Received: 12.02.2015
Accepted after revision: 30.04.2015
Published online: 23.06.2015
used successfully for arylations, alkenylations, and alky-
nylations of various arenes and heteroarenes.8e,9 However,
the recovery of the catalyst is a problem in these reactions.
Copper catalysts in a nanoparticulate form that is suitable
for recyclization have also been used, making the synthetic
procedures greener.10 Nanoparticulate copper(II) oxide has
been used11 for C–H bond activation of various heterocy-
cles, such as 1,3-azoles, benzoxazole, benzothiazole, and
benzimidazole, and of N-aryl-N′-arylidinehydrazines. How-
ever, to our knowledge, nanoparticulate copper catalysts
have not previously been used for transformations of 1,3,4-
oxadiazoles, although a general copper catalyst has been
used.7a,b,9i
Nanoparticles have recently gained considerable impor-
tance as heterogeneous catalysts because of their high spe-
cific surface area and their good stability and recyclization
properties.11 Nanoparticulate copper(II) oxide is an import-
ant commercially available catalyst that has been used to
catalyze various useful transformations, including carbon–
carbon and carbon–heteroatom bond formation.10–12 Here,
we used this catalyst for the conversion of 1,3,4-oxadi-
azoles.
We discovered that treatment of 1,3,4-oxadiazoles 1
with aryl halides 2 or alkenyl halides 3 in the presence of
copper(II) oxide nanoparticles gives 2-aryl-1,3,4-oxadi-
azoles (4) and 2-alkenyl-1,3,4-oxadiazoles 5, respectively
(Scheme 1).
We initially optimized the conditions of the synthesis
by using 2-phenyl-1,3,4-oxadiazole (1a) and 1-ethyl-4-io-
dobenzene (2a) with various bases, solvents, and ligands
(Table 1). Effects of various amounts of copper(II) oxide
nanoparticles and changes in the temperature and time for
the reaction were also studied. The best yields were ob-
tained by using nanoparticulate copper(II) oxide (10 mol%),
potassium carbonate (2 equiv), and triphenylphosphine (30
DOI: 10.1055/s-0034-1380923; Art ID: ss-2015-z0106-op
Abstract 2-Aryl- and 2-alkenyl-1,3,4-oxadiazoles were efficiently syn-
thesized in high yields by treatment of 1,3,4-oxadiazoles with aryl or
alkenyl halides, respectively, in the presence of copper(II) oxide
nanoparticles as a catalyst. The reusability of the catalyst is an import-
ant advantage in relation to practical applications of this synthesis.
Key words oxadiazoles, copper, catalysis, nanoparticles, arylations,
alkenylations
Because of their valuable applications in pharmaceuti-
cal and material sciences, oxadiazoles have recently attract-
ed considerable attention from chemists and biologists.
Oxadiazoles can serve as bioisosteres of amides and esters.2
They are also used as anticonvulsant and antimicrobial
agents.3 Some oxadiazoles possess good electron-transport-
ing and hole-blocking abilities,4 and they have applications
in the field of organic electronics.5 2-Biphenyl-4-yl-5-(4-
tert-butylphenyl)-1,3,4-oxadiazole (BPD), 2,2′-(1,3-phenyl-
ene)bis[5-(4-tert-butylphenyl)-1,3,4-oxadiazole] (OXD 7),
and related compounds are important examples.5a,6 An im-
provement in the synthesis of oxadiazole derivatives is
therefore highly desirable. In continuation of our work7 on
the synthesis of these compounds, we report an efficient
preparation of 2-aryl and 2-alkenyl derivatives of 1,3,4-oxa-
diazoles by using copper(II) oxide nanoparticles as a cata-
lyst.
The transformation of a C–H bond to a C–C bond in the
presence of a metal catalyst is an important theme in cur-
rent organic synthesis.7c,8 Various metal catalysts, such as
palladium, rhodium, and ruthenium, have been used in this
transformation. More recently, however, expensive metal
catalysts have been replaced with more-abundant and less-
expensive ones. Copper is one such catalyst that has been
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Synthesis
Table 1 Optimization of the Copper-Catalyzed Cross-Coupling of
2-Phenyl-1,3,4-Oxadiazole (1a) with 1-Ethyl-4-iodobenzene (2a)a
nano CuO (10 mol%)
Ph3P (30 mol%)
K2CO3 (2 equiv)
N
O
N
Ar2X
2
Ar2
N
N
diglyme, reflux
10–24 h
Ar1
nano CuO (10 mol%)
Ph3P (30 mol%)
K2CO3 (2 equiv)
4
N
N
Ar
O
70–85%
1a
N
O
N
Ar1
nano CuO (10 mol%)
Ph3P (30 mol%)
K2CO3 (2 equiv)
O
+
Ar2
N
N
Diglyme, reflux
10–24 h
1
Ar
4aa
I
Ar1
diglyme, reflux
18–24 h
O
X
Ar2
3
5
2a
71–81%
Entry
Base
Solvent
Ligand
Yieldb (%)
Scheme 1 Copper-catalyzed C–C coupling
1
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
DMF
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
52
DMSO
47
mol%) in refluxing diglyme (3 mL) for 12 hours (Table 1, en-
try 6). Increasing the amount of catalyst produced no signif-
icant change in the yield, but in the absence of the catalyst,
the yield was low (20%). Various bases, such as potassium
carbonate, cesium carbonate, lithium tert-butoxide, and po-
tassium tert-butoxide, and various solvents, such as N,N-di-
methylformamide, dimethyl sulfoxide, 1,4-dioxane, tolu-
ene, xylene, and tetrahydrofuran, were also used, but yields
were unsatisfactory. The reaction did not proceed in the ab-
sence of a ligand; triphenylphosphine was found to be the
most suitable ligand for this conversion. The reaction also
failed to take place at room temperature; the best results
were obtained under reflux conditions. The yield was 5%
lower when the reaction was conducted with 1-bromo-4-
ethylbenzene instead of 1-ethyl-4-iodobenzene.
3
1,4-dioxane
toluene
xylene
24
4
trace
trace
85
5
6
diglyme
diglyme
THF
7
63
8
K2CO 3
K2CO 3
K2CO 3
Cs2CO3
Cs2CO3
t-BuOLi
t-BuOK
Na2CO3
NRc
NRd
39
9
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
10
11
12
13
14
15
2,2′-bipye
1,10-phenf
DMEDAg
TMEDAh
2,2′-bipy
Ph3P
30
25
trace
trace
66
Having optimized the reaction conditions, we prepared
several 2-aryl-1,3,4-oxadiazoles 4 by means of nanopartic-
ulate copper(II) oxide-catalyzed cross-coupling of 1,3,4-
oxadiazoles 1 and aryl iodides 2 (Table 2). The starting oxa-
diazoles 1 contained either aromatic or heteroaromatic nu-
clei. The aryl iodides also contained aromatic or heteroaro-
matic rings. 1-Iodonaphthalene underwent the conversion
smoothly (Table 2, entry 2). The transformation was com-
pleted within 10–24 hours, and the yields were 70–85%.
A similar conversion was also used in the synthesis of 2-
alkenyl-1,3,4-oxadiazoles (5) by treatment of 1,3,4-oxadi-
azoles 1 with alkenyl iodides 3 in the presence of copper(II)
oxide nanoparticles (Scheme 1 and Table 2). The reaction
was completed within 18–24 hours, and the yields were
71–81%. The E-isomers were formed exclusively.
a Reaction conditions: 2-phenyl-1,3,4-oxadiazole (1a; 0.7 mmol), 1-ethyl-4-
iodobenzene (2a; 1.0 mmol), nanoparticulate CuO (10 mol%), K2CO3 (2
equiv), diglyme (3mL), Ph3P (30 mol%), reflux.
b Isolated yield after column chromatography.
c No reaction.
d The reaction was carried out at r.t. (27 °C).
e 2,2′-Bipyridine.
f 1,10-Phenanthroline.
g N,N-Dimethylethylenediamine.
h N,N,N′-Trimethylethylenediamine.
In conclusion, we have developed a simple, efficient and
improved synthesis of 2-aryl- and 2-alkenyl-1,3,4-oxadi-
azoles by using copper(II) oxide nanoparticles as a recycla-
ble catalyst.
Nanoparticulate CuO was obtained from Sigma Aldrich [particle
size: <50 nm (TEM), surface area: 29 m2/g, CAS number 1317-38-0].
Ph3P was purchased from Sigma Aldrich [CAS number 603-35-0] and
diglyme from Finar Limited [CAS number 111-46-6)] and used direct-
ly. Solvents were dried by using CaCl2 and Na. Melting points were de-
termined on a Buchi 510 apparatus and are uncorrected. IR spectra
were recorded on a Perkin-Elmer RX FT-IR spectrophotometer. 1H
NMR and 13C NMR spectra were recorded on a Gemini Varian spec-
trometer at 200 MHz and 50 MHz respectively. Chemical shifts (δ) are
reported relative to TMS as an internal standard. Mass spectra were
recorded on a Micromass VG-Autospec spectrometer operated in the
[M + H]+ mode. Elemental analyses were performed by using a Vario
Micro Cube C, H, N, S, O analyzer (Elementar, Germany).
All the products were characterized by spectroscopy
and by comparison to known compounds.7a,c When the
nanoparticulate catalyst was recovered and reused, no sig-
nificant change in its catalytic activity was observed. For
example, in the reaction of 2-phenyl-1,3,4-oxadiazole (1a)
with 1-ethyl-4-iodobenzene (2a) in the presence of
nanoparticulate copper(II) oxide, the yields from the first,
second, and third cycles of catalyst use were 85, 82, and 78%
respectively.
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Synthesis
Table 2 Copper-Catalyzed Cross-Coupling of Various 1,3,4-Oxadiazoles 1 with Aryl Halides 2 or Alkenyl Halides 3a
Entry
Oxadiazole
Halide
Product
Time (h)
12
Yieldb (%)
N
O
N
O
N
N
N
N
N
I
1
85
2a
4aa
4aa
4ab
4ac
1a
1a
1a
1a
N
O
N
O
N
N
N
Br
1a
15
16
14
80
77
72
2a′
N
O
N
O
I
2
2b
N
O
N
O
I
S
3
S
2c
N
O
N
O
N
N
I
4
5
17
18
73
70
Cl
1b
Cl
4bb
2b
N
O
N
O
N
N
F
F
I
2d
Cl
1b
Cl
4bd
N
N
N
N
N
N
O
O
I
6
21
83
2e
F3C
F3C
1c
4ce
N
O
N
O
N
N
N
I
N
7
8
19
14
84
72
2f
F3C
1c
F3C
4cf
N
O
N
O
N
N
F
F
I
2d
O
O
1d
4dd
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Synthesis
Table 2 (continued)
Entry
Oxadiazole
Halide
Product
Time (h)
20
Yieldb (%)
N
O
N
O
N
N
N
I
9
79
3a
1a
1a
5aa
5ab
N
O
N
O
N
I
Ph
Ph
10
11
24
18
76
74
3b
N
N
O
N
N
I
O
3a
Cl
1b
Cl
5ba
N
N
O
N
N
I
O
Ph
Ph
12
13
20
16
81
78
3b
Cl
1b
Cl
5bb
N
N
N
N
I
O
O
3a
F3C
F3C
5ca
1c
N
N
O
N
N
I
O
Ph
Ph
14
15
16
24
22
24
80
73
71
3b
F3C
1c
F3C
5cb
N
N
N
N
N
I
O
O
3a
1e
1e
5ea
5eb
N
O
N
N
I
Ph
O
Ph
3b
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Synthesis
Table 2 (continued)
Entry
17
Oxadiazole
Halide
Product
Time (h)
18
Yieldb (%)
N
N
O
N
N
N
I
O
77
3a
MeO
1f
MeO
5fa
N
O
N
O
N
I
Ph
Ph
18
20
72
3b
MeO
1f
MeO
5fb
a Reaction conditions: 1,3,4-oxadiazole (1; 0.25 mmol), aryl/alkenyl iodide (2 or 3; 0.50mmol), nanoparticulate CuO (10 mol%), K2CO3 (2 equiv),
diglyme (3 mL), Ph3P (30 mol%).
b Isolated yield after column chromatography.
Arylation of 1,3,4-Oxadiazoles with Aryl Halides; General Proce-
dure
2-(1-Naphthyl)-5-phenyl-1,3,4-oxadiazole (4ab) (Table 2, Entry 2)
Brown solid; yield: 52 mg (77%); mp 113–115 °C.
A 10 mL round-bottomed flask was charged with the appropriate 2-
aryl-1,3,4-oxadiazole 1 (0.25 mmol), aryl halide 2 (0.50 mmol),
nanoparticulate CuO (10 mol%) , Ph3P (30 mol%), K2CO3 (2 equiv), and
diglyme (3.0 mL). The mixture was stirred under reflux until the
starting materials were consumed (TLC). The mixture was then al-
lowed to cool and extracted with EtOAc (2 × 10 mL). The organic ex-
tracts were combined, dried (Na2SO4), and concentration in vacuo.
The residue was purified by column chromatography (silica gel).
IR (KBr): 2395, 1605, 1547, 1449, 1267 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.49 (m, 1 H, Ar-H), 8.22–8.16 (m, 3 H,
Ar-H), 7.93 (d, J = 8.0 Hz, 2 H, Ar-H), 7.84 (m, 1 H, Ar-H), 7.59–7.50 (m,
5 H, Ar-H).
13C NMR (50 MHz, CDCl3): δ = 165.0, 134.9, 133.1, 131.8, 129.1, 129.0,
128.0, 127.9, 127.3, 127.2, 127.1, 124.2, 123.4, 121.1.
MS (ESI): m/z = 273 [M + H]+.
Anal. Calcd for C18H12N2O: C, 79.39; H, 4.44; N, 10.29. Found: C, 79.52;
H, 4.47; N, 10.33.
Recycling of the Catalyst
A 50 mL round-bottomed flask was charged with 2-phenyl-1,3,4-oxa-
diazole (1a; 510 mg, 3.5 mmol), 4-ethylphenyl iodide (2a; 1160 mg,
5.0 mmol), nanoparticulate CuO (40 mg, 10%), Ph3P (395 mg, 30
mol%), K2CO3 (690 mg, 10 equiv), and diglyme (15 mL). The mixture
was stirred under reflux for 12 h until the starting materials were
consumed (TLC). The mixture was then allowed to cool and extracted
with EtOAc (2 × 30 mL). The CuO nanoparticles were removed centrif-
ugation, washed with H2O, and dried in an oven at 120 °C for 3 h. Con-
centration of the extract in vacuo followed by column chromatogra-
phy (silica gel) gave oxadiazole 4aa; yield: 742 mg (85%). When the
recovered CuO nanoparticles were reused, the yields for the second
and third cycles were 82% (715 mg) and 78% (681 mg), respectively.
2-Phenyl-5-(3-thienyl)-1,3,4-oxadiazole (4ac) (Table 2, Entry 3)
Light-yellow solid; yield: 41 mg (72%); mp 117–119 °C.
IR (KBr): 2402, 1590, 1481, 1448, 1261 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.13–8.07 (m, 3 H, Ar-H), 7.72 (m, 1 H,
Ar-H), 7.55–7.42 (m, 4 H, Ar-H).
13C NMR (50 MHz, CDCl3): δ = 163.9, 161.3, 131.8, 129.1, 127.5, 126.9,
126.1, 125.3, 123.9.
MS (ESI): m/z = 229 [M + H]+.
Anal. Calcd for C12H8N2OS: C, 63.14; H, 3.53; N, 12.27. Found: C, 63.22;
H, 3.57; N, 12.24.
2-(4-Ethylphenyl)-5-phenyl-1,3,4-oxadiazole (4aa) (Table 2, Entry
1)
2-(4-Chlorophenyl)-5-(1-naphthyl)-1,3,4-oxadiazole (4bb) (Table
2, Entry 4)
White solid; yield: 53 mg (85%); mp 114–116 °C.
White solid; yield: 55 mg (73%); mp 163–165 °C.
IR (KBr): 2397, 1612, 1548, 1488, 1269 cm–1
.
IR (KBr): 2412, 1603, 1474, 1270 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.17–8.10 (m, 2 H, Ar-H), 8.02 (d, J =
8.0 Hz, 2 H, Ar-H), 7.58–7.50 (m, 3 H, Ar-H), 7.32 (d, J = 8.0 Hz, 2 H, Ar-
H), 2.72 (q, J = 7.0 Hz, 2 H, –CH2–), 1.28 (t, J = 7.0 Hz, 3 H, –CH3).
13C NMR (50 MHz, CDCl3): δ = 164.8, 164.5, 148.8, 131.8, 129.1, 128.8,
127.2, 127.1, 124.1, 121.2, 29.0, 15.2.
1H NMR (200 MHz, CDCl3): δ = 8.58 (m, 1 H, Ar-H), 8.19 (d, J = 8.0 Hz,
1 H, Ar-H), 8.11 (d, J = 8.0 Hz, 2 H, Ar-H), 7.94 (d, J = 8.0 Hz, 2 H, Ar-H),
7.85 (d, J = 8.0 Hz, 1 H, Ar-H), 7.59–7.50 (m, 4 H, Ar-H).
13C NMR (50 MHz, CDCl3): δ = 165.0, 163.9, 138.1, 134.5, 132.7, 129.4,
128.9, 128.7, 128.1, 127.9, 127.8, 127.3, 127.1, 123.0, 122.5, 120.8.
MS (ESI): m/z = 307, 309 [M + H]+.
MS (ESI): m/z = 251 [M + H]+.
Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.86;
H, 5.67; N, 11.22.
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Synthesis
Anal. Calcd for C18H11ClN2O: C, 70.48; H, 3.61; N, 9.13. Found: C,
70.37; H, 3.57; N, 9.16.
2-Phenyl-5-[(E)-2-phenylvinyl]-1,3,4-oxadiazole (5aa) (Table 2, En-
try 9)
Brown solid; yield: 48 mg (79%); mp 125–127 °C.
2-(4-Chlorophenyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole (4bd) (Ta-
ble 2, Entry 5)
IR (KBr): 2390, 1643, 1521, 1445, 1265 cm–1
1H NMR (200 MHz, CDCl3): δ = 8.12 (d, J = 8.0 Hz, 2 H), 7.62–7.50 (m, 6
H), 7.49–7.38 (m, 3 H), 7.11 (d, J = 14.0 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 164.1, 139.0, 135.0, 131.8, 130.1, 129.1,
127.5, 127.2, 123.9, 110.2.
.
White solid; yield: 48 mg (70%); mp 207–209 °C.
IR (KBr): 2408, 1606, 1489, 1229 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.18–8.10 (m, 2 H, Ar-H), 8.04 (d, J =
8.0 Hz, 2 H, Ar-H), 7.51 (d, J = 8.0 Hz, 2 H, Ar-H), 7.21 (t, J = 8.0 Hz, 2 H,
Ar-H).
13C NMR (50 MHz, CDCl3): δ = 166.4 (d, J = 280.0 Hz), 164.0, 137.2,
129.6, 129.2 (d, J = 100 Hz), 128.4, 122.8, 120.2, 116.9 (d, J = 25.0 Hz).
MS (ESI): m/z = 249 [M + H]+.
Anal. Calcd for C16H12N2O: C, 77.40; H, 4.87; N, 11.28. Found: C, 77.54;
H, 4.83; N, 11.31.
MS (ESI): m/z = 275, 277 [M + H]+.
2-[(E)-2-Biphenyl-4-ylvinyl]-5-phenyl-1,3,4-oxadiazole (5ab) (Ta-
ble 2, Entry 10)
Anal. Calcd for C14H8ClFN2O: C, 61.22; H, 2.94; N, 10.20. Found: C,
61.34; H, 2.91; N, 10.16.
White solid; yield: 61 mg (76%); mp 130–132 °C.
IR (KBr): 2391, 1643, 1549, 1477, 1278 cm–1
1H NMR (200 MHz, CDCl3): δ = 8.18–8.02 (m, 3 H), 7.70–7.31 (m, 12
H), 7.12 (d, J = 14.0 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 164.3, 142.8, 140.2, 138.7, 133.9, 132.8,
129.0, 128.9, 127.8, 127.6, 127.4, 126.7, 124.1, 109.9.
.
3-{5-[4-(Trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}pyridine
(4ce) (Table 2, Entry 6)
Brown solid; yield: 60 mg (83%); mp 165–167 °C.
IR (KBr): 2405, 1605, 1547, 1492, 1323 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 9.41 (d, J = 2.0 Hz, 1 H, Ar-H), 8.84 (dd,
J = 7.0, 2.0 Hz, 1 H, Ar-H), 8.45 (dt, J = 8.0, 2.0 Hz, 1 H, Ar-H), 8.31 (d,
J = 8.0 Hz, 2 H, Ar-H), 7.84 (d, J = 8.0 Hz, 2 H, Ar-H), 7.52 (dd, J = 8.0,
7.0 Hz, 1 H, Ar-H).
MS (ESI): m/z = 325 [M + H]+.
Anal. Calcd for C22H16N2O: C, 81.46; H, 4.97; N, 8.64. Found: C, 81.35;
H, 4.93; N, 8.68.
13C NMR (50 MHz, CDCl3): δ = 164.2, 163.5, 152.9, 148.2, 134.9, 133.5,
128.0, 127.3, 126.9, 124.0, 122.1 (q, J = 227.0 Hz), 120.2.
MS (ESI): m/z = 292 [M + H]+.
2-(4-Chlorophenyl)-5-[(E)-2-phenylvinyl]-1,3,4-oxadiazole (5ba)
(Table 2, Entry 11)
White solid; yield: 66 mg (74%); mp 140–142 °C.
Anal. Calcd for C14H8F3N3O: C, 57.74; H, 2.77; N, 14.43. Found: C,
57.63; H, 2.73; N, 14.46.
IR (KBr): 2386, 1643, 1519, 1480, 1263 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.01 (d, J = 8.0 Hz, 2 H), 7.63–7.31 (m, 8
H), 7.02 (d, J = 14.0 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 163.1, 139.3, 138.1, 134.5, 130.2, 129.8,
4-{5-[4-(Trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}pyridine
(4cf) (Table 2, Entry 7)
128.9, 128.2, 127.4, 125.5, 122.6, 109.8.
MS (ESI): m/z = 283, 285 [M + H]+.
Brown solid; yield: 61 mg (84%); mp 168–170 °C.
IR (KBr): 2394, 1614, 1498, 1242 cm–1
.
Anal. Calcd for C16H11ClN2O: C, 67.97; H, 3.92; N, 9.91. Found: C,
67.85; H, 3.88; N, 9.87.
1H NMR (200 MHz, CDCl3): δ = 8.88 (d, J = 7.0 Hz, 2 H, Ar-H), 8.30 (d,
J = 8.0 Hz, 2 H, Ar-H), 7.99 (d, J = 7.0 Hz, 2 H, Ar-H), 7.82 (d, J = 8.0 Hz,
2 H, Ar-H).
2-[(E)-2-Biphenyl-4-ylvinyl]-5-(4-chlorophenyl)-1,3,4-oxadiazole
(5bb) (Table 2, Entry 12)
13C NMR (50 MHz, CDCl3): δ = 164.2, 163.5, 151.1, 144.3, 131.0, 127.9,
126.3, 126.1, 124.0 (q, J = 227.0 Hz), 120.6.
MS (ESI): m/z = 292 [M + H]+.
White solid; yield: 72 mg (81%); mp 158–160 °C.
IR (KBr): 2396, 1639, 1509, 1476, 1275 cm–1
.
Anal. Calcd for C14H8F3N3O: C, 57.74; H, 2.77; N, 14.43. Found: C,
57.66; H, 2.73; N, 14.41.
1H NMR (200 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 2 H), 7.72–7.61 (m, 7
H), 7.54–7.35 (m, 5 H), 7.12 (d, J = 14.0 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 164.8, 143.2, 140.1, 139.0, 138.2, 133.7,
2-(4-Fluorophenyl)-5-(2-furyl)-1,3,4-oxadiazole (4dd) (Table 2, En-
129.3, 128.9, 128.0, 127.9, 127.3, 126.6, 122.9, 109.5.
try 8)
Brown solid; yield: 41 mg (72%); mp 130–132 °C.
MS (ESI): m/z = 359, 361 [M + H]+.
IR (KBr): 2412, 1632, 1605, 1497, 1233 cm–1
1H NMR (200 MHz, CDCl3): δ = 8.20–8.08 (m, 2 H, Ar-H), 7.62 (m, 1 H,
.
Anal. Calcd for C22H15ClN2O: C, 73.64; H, 4.21; N, 7.81. Found: C,
73.72; H, 4.25; N, 7.78.
Ar-H), 7.28–7.15 (m, 3 H, Ar-H), 6.61 (m, 1 H, Ar-H).
13C NMR (50 MHz, CDCl3): δ = 165.0 (d, J = 280.0 Hz), 157.7, 145.9,
129.4 (d, J = 5.0 Hz), 126.8, 120.1, 116.0 (d, J = 30.0 Hz), 115.2, 112.3.
2-[(E)-2-Phenylvinyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadi-
azole (5ca) (Table 2, Entry 13)
Brown solid; yield: 61 mg (78%); mp 146–148 °C.
MS (ESI): m/z = 231 [M + H]+.
IR (KBr): 2382, 1643, 1518, 1329, 1163 cm–1
.
Anal. Calcd for C12H7FN2O2: C, 62.61; H, 3.07; N, 12.17. Found: C,
62.72; H, 3.04; N, 12.14.
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Synthesis
1H NMR (200 MHz, CDCl3): δ = 8.26 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.0
MS (ESI): m/z = 279 [M + H]+.
Hz, 2 H), 7.64–7.52 (m, 3 H), 7.46–7.38 (m, 3 H), 7.09 (d, J = 14.0 Hz, 1
H).
13C NMR (50 MHz, CDCl3): δ = 162.9, 139.9, 134.4, 130.1, 129.2, 127.5,
127.2, 126.1, 126.0 (q, J = 227.0 Hz), 109.2.
MS (ESI): m/z = 317 [M + H]+.
Anal. Calcd for C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C,
73.46; H, 5.10; N, 10.03.
2-[(E)-2-Biphenyl-4-ylvinyl]-5-(4-methoxyphenyl)-1,3,4-oxadi-
azole (5fb) (Table 2, Entry 18)
White solid; yield: 63 mg (72%); mp 164–166 °C.
Anal. Calcd for C17H11F3N2O: C, 64.56; H, 3.51; N, 8.86. Found: C,
64.42; H, 3.47; N, 8.89.
IR (KBr): 2394, 1610, 1494, 1451, 1256 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.05 (d, J = 8.0 Hz, 2 H), 7.72–7.54 (m, 7
H), 7.49–7.30 (m, 4 H), 7.10 (d, J = 14.0 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1
H), 3.91 (s, 3 H).
2-[(E)-2-Biphenyl-4-ylvinyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-
oxadiazole (5cb) (Table 2, Entry 14)
Brown solid; yield: 77 mg (80%); mp 201–203 °C.
13C NMR (50 MHz, CDCl3): δ = 162.7, 142.9, 140.0, 137.9, 134.1, 128.9,
128.8, 128.0, 127.9, 127.7, 127.1, 116.6, 114.5, 109.9, 55.2.
IR (KBr): 2372, 1636, 1414, 1331, 1124 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.26 (d, J = 8.0 Hz, 2 H), 7.82 (d, J = 8.0
MS (ESI): m/z = 355 [M + H]+.
Hz, 2 H), 7.73–7.55 (m, 7 H), 7.49–7.31 (m, 3 H), 7.12 (d, J = 14.0 Hz, 1
H).
13C NMR (50 MHz, CDCl3): δ = 162.9, 143.1, 140.0, 139.3, 133.2, 128.9,
128.1, 128.0, 127.8, 127.2, 127.0, 126.1, 125.8 (q, J = 227.0 Hz), 111.9,
109.3.
Anal. Calcd for C23H18N2O2: C, 77.95; H, 5.12; N, 7.90. Found: C, 77.83;
H, 5.15; N, 7.94.
Acknowledgment
MS (ESI): m/z = 393 [M + H]+.
The authors thank CSIR, New Delhi, for financial assistance.
Anal. Calcd for C23H15F3N2O: C, 70.40; H, 3.85; N, 7.14. Found: C,
70.52; H, 3.81; N, 7.17.
References
5-[(E)-2-Phenylvinyl]-2-(4-tolyl)-1,3,4-oxadiazole (5ea) (Table 2,
Entry 15)
(1) Part 237 in the series Studies on Novel Synthetic Methodologies.
(2) Leung, D.; Du, W.; Hardouin, C.; Cheng, H.; Hwang, I.; Cravatt, B.
F.; Boger, D. L. Bioorg. Med. Chem. Lett. 2005, 15, 1423.
(3) (a) Rostom, S. A. F.; Shalaby, M. A.; El-Demellawy, M. A. Eur. J.
Med. Chem. 2003, 38, 959. (b) Jha, K. K.; Samad, A.; Kumar, Y.;
Shaharyar, M.; Khosa, R. L.; Jain, J.; Kumar, V.; Sing, P. Eur. J. Med.
Chem. 2010, 45, 4963. (c) Singh, P.; Jangra, P. K. Der Chem. Sin.
2010, 1, 118.
Light-yellow solid; yield: 65 mg (73%); mp 127–129.
IR (KBr): 2378, 1642, 1492, 1443, 1258 cm–1
1H NMR (200 MHz, CDCl3): δ = 7.99 (d, J = 8.0 Hz, 2 H), 7.60–7.52 (m, 3
H), 7.41–7.28 (m, 5 H), 7.05 (d, J = 14.0 Hz, 1 H), 2.42 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 164.1, 142.3, 138.8, 134.9, 130.1, 130.0,
.
129.2, 127.6, 126.9, 121.1, 110.0, 21.2.
(4) Singh, S.; Sharma, L. K.; Saraswat, A.; Siddiqui, I. R.; Kheri, H. K.;
Singh, R. K. P. RSC Adv. 2013, 3, 4237.
(5) (a) Mitschke, U.; Bäuerle, P. J. Mater. Chem. 2000, 10, 1471.
(b) Zarudnitskii, E. V.; Pervak, I. I.; Merkulov, A. S.; Yurchenko, A.
A.; Tolmachev, A. A. Tetrahedron 2008, 64, 10431.
MS (ESI): m/z = 263 [M + H]+.
Anal. Calcd for C17H14N2O: C, 77.95; H, 5.12; N, 7.90. Found: C, 77.81;
H, 5.15; N, 7.87.
2-[(E)-2-Biphenyl-4-ylvinyl]-5-(4-tolyl)-1,3,4-oxadiazole (5eb) (Ta-
ble 2, Entry 16)
(6) (a) Yang, X.; Müller, D. C.; Neher, D.; Meerholz, K. Adv. Mater.
(Weinheim, Ger.) 2006, 18, 948. (b) He, G. S.; Tan, L.-S.; Zhang,
Q.; Prasad, P. N. Chem. Rev. 2008, 108, 1245.
Light-yellow solid; yield: 60 mg (71%); mp 150–152 °C.
(7) (a) Das, B.; Reddy, G. C.; Balasubramanyam, P.; Salvanna, N. Tet-
rahedron 2012, 68, 300. (b) Salvanna, N.; Reddy, G. C.; Rao, B. R.;
Das, B. RSC Adv. 2013, 3, 20538. (c) Salvanna, N.; Reddy, G. C.;
Das, B. Tetrahedron 2013, 69, 2220. (d) Salvanna, N.; Das, B.
Synlett 2014, 25, 2033.
IR (KBr): 2394, 1638, 1490, 1410, 1268 cm–1
1H NMR (200 MHz, CDCl3): δ = 8.01 (d, J = 8.0 Hz, 2 H), 7.68–7.57 (m, 7
H), 7.49–7.30 (m, 5 H), 7.10 (d, J = 14.0 Hz, 1 H), 2.43 (m, 3 H).
.
13C NMR (50 MHz, CDCl3): δ = 164.5, 142.8, 142.5, 140.2, 138.4, 133.9,
129.9, 129.1, 128.0, 127.9, 127.8, 127.0, 121.1, 110.0, 21.8.
MS (ESI): m/z = 339 [M + H]+.
(8) For some recent examples, see: (a) Yanagisawa, S.; Sudo, T.;
Noyori, R.; Itami, K. J. Am. Chem. Soc. 2006, 128, 11748.
(b) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 12072. (c) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008,
73, 7428. (d) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi,
Z.-J. Angew. Chem. Int. Ed. 2008, 47, 1473. (e) Besselièvre, F.;
Piguel, S.; Mahuteau-Betzer, F.; Grierson, D. S. Org. Lett. 2008,
10, 4029. (f) Monnier, F.; Turtaut, F.; Duroure, L.; Taillefer, M.
Org. Lett. 2008, 10, 3203. (g) Mukai, T.; Hirano, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2009, 74, 6410. (h) Ackermann, L.;
Althammer, A.; Fenner, S. Angew. Chem. Int. Ed. 2009, 48, 201.
(i) Join, B.; Yamamoto, T.; Itami, K. Angew. Chem. Int. Ed. 2009,
48, 3644. (j) Kobayashi, O.; Uraguchi, D.; Yamakawa, T. Org. Lett.
2009, 11, 2679. (k) Verrier, C.; Hoarau, C.; Marsais, F. Org.
Anal. Calcd for C23H18N2O: C, 81.53; H, 5.36; N, 8.28. Found: C, 81.67;
H, 5.39; N, 8.32.
2-(4-Methoxyphenyl)-5-[(E)-2-phenylvinyl]-1,3,4-oxadiazole (5fa)
(Table 2, Entry 17)
White solid; yield: 53 mg (77%); mp 135–137 °C.
IR (KBr): 2382, 1609, 1493, 1449, 1257 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.07 (d, J = 8.0 Hz, 2 H), 7.65–7.52 (m, 3
H), 7.48–7.31 (m, 4 H), 7.02 (d, J = 14.0 Hz, 2 H), 3.90 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 162.9, 138.8, 135.1, 130.0, 129.1, 128.9,
127.8, 116.3, 114.8, 110.2, 55.7.
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Biomol. Chem. 2009, 7, 647. (l) Miyasaka, M.; Hirano, K.; Satoh,
T.; Miura, M. J. Org. Chem. 2010, 75, 5421. (m) Liao, Q.; Zhang, L.;
Li, S.; Xi, C. Org. Lett. 2011, 13, 228.
(m) Tomashenko, O. A.; Escudero-Adán, E. C.; Martínez Bel-
monte, M.; Grushin, V. V. Angew. Chem. Int. Ed. 2011, 50, 7655.
(n) Zhao, X.; Wu, G.; Zang, Y.; Wang, J. J. Am. Chem. Soc. 2011,
133, 3296.
(9) (a) Hilf, C.; Bosold, F.; Harms, K.; Marsch, M.; Boche, G. Chem.
Ber. 1997, 130, 1213. (b) Sánchez, R. S.; Zhuravlev, F. A. J. Am.
Chem. Soc. 2007, 129, 5824. (c) Rout, L.; Sen, T. K.;
Punniyamurthy, T. Angew. Chem. Int. Ed. 2007, 46, 5583.
(d) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007,
63, 1568. (e) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
1128. (f) Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008,
47, 1932. (g) Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.;
Mandal, S.; Mitra, R.; Saha, P.; Punniyamurthy, T. J. Org. Chem.
2009, 74, 1971. (h) Pirrung, M. C.; Ghorai, S.; Ibarra-Rivera, T. R.
J. Org. Chem. 2009, 74, 4110. (i) Kawano, T.; Yashizumi, T.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 3072.
(j) Monguchi, D.; Yamamura, A.; Fujiwara, T.; Somete, T.; Mori,
A. Tetrahedron Lett. 2010, 51, 850. (k) Polshettiwar, V.; Varma, R.
S. Green Chem. 2010, 12, 743. (l) Xu, J.; Luo, D.-F.; Xiao, B.; Liu,
Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L. Chem. Commun. 2011, 47, 4300.
(10) (a) Zhang, W.; Zeng, Q.; Zhang, X.; Tian, Y.; Yue, Y.; Guo, Y.;
Wang, Z. J. Org. Chem. 2011, 76, 4741. (b) Zhang, W.; Tian, Y.;
Zhao, N.; Wang, Y.; Li, J.; Wang, Z. Tetrahedron 2014, 70, 6120.
(c) Murty, M. S. R.; Penthala, R.; Buddana, S. K.; Prakasham, R.
S.; Das, P.; Polepalli, S.; Jain, N.; Bojja, S. Med. Chem. Res. 2014,
23, 4579.
(11) (a) Durán Pachón, L.; van Maarseveen, J. H.; Rothenberg, G. Adv.
Synth. Catal. 2005, 347, 811. (b) Zhang, W.; Qi, H.; Li, L.; Wang,
X.; Chen, J.; Peng, K.; Wang, Z. Green Chem. 2009, 11, 1194.
(c) Sreedhar, B.; Arundhathi, R.; Reddy, P. L.; Kantam, M. L. J.
Org. Chem. 2009, 74, 7951. (d) Reddy, V. P.; Kumar, A. V.;
Swapna, K.; Rao, K. R. Org. Lett. 2009, 11, 1697. (e) Polshettiwar,
V.; Varma, R. S. Green Chem. 2010, 12, 743.
(12) Ranu, B. C.; Dey, R.; Chatterjee, T.; Ahammed, S. ChemSusChem
2012, 5, 22.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2831–2838