Palladium-Catalyzed Decarboxylative Cross-Coupling of 1,3,4-Oxa-diazoles with Alkynoic Acids: A Simple Route for the Preparation of 2-Alkynylated 1,3,4-Oxadiazoles

Article abstract of DOI:10.1055/s-0036-1588115

For the first time 2-alk-1-ynyl-5-(het)aryl-1,3,4-oxadiazole derivatives have been synthesized by the decarboxylative cross-coupling of alk-2-ynoic acids with 2-(het)aryl-1,3,4-oxadiazoles, employing palladium(II) chloride as the catalyst and silver(I) oxide as an oxidant with 1,3-bis(diphenylphosphanyl)propane as a ligand. Products were formed in high yields with no byproduct.

Full text of DOI:10.1055/s-0036-1588115

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–E
paper
A
L. M. Reddy et al.
Paper
Synthesis
Palladium-Catalyzed Decarboxylative Cross-Coupling of 1,3,4-Oxa-
diazoles with Alkynoic Acids: A Simple Route for the Preparation
of 2-Alkynylated 1,3,4-Oxadiazoles
L. Madhava Reddya
P. Raghavendar Reddyb
Ch. Krishna Reddy*a
N
N
PdCl2, Ag2O, dppp
toluene, 80 °C, 10 h
N
N
R2
HOOC
R2
R1
O
R1
O
51–75%
R
1 = aryl, heteroaryl
R2 = alkyl, aryl
a Department of Chemistry, University College of Science,
Osmania University, Hyderabad, Telangana, 500007, India
krreddych.ou@gmail.com
b Natural Products Chemistry Division, CSIR-Indian Institute
of Chemical Technology, Hyderabad, 500007, India
Received: 07.09.2016
Accepted after revision: 11.11.2016
Published online: 15.12.2016
Carboxylic acid substrates were reported to be success-
ful coupling counterparts, with heterocyclic compounds9 as
one of the reaction partners, and they are commercially
available and inexpensive. Decarboxylative direct couplings
are of great interest, as they reduce the amount of toxic side
products,10 produce only CO2, and favor purification of the
product.
The common methods for formation of 2-alkynyl-1,3,4-
oxadiazoles11 include the use of alkynyl halides, terminal
alkynes, gem-dihaloalkenes, and copper acetylides. In the
present study we have demonstrated a benign alternative
method, decarboxylative cross-coupling of alkynoic acids
with 1,3,4-oxadiazoles in the presence of palladium chlo-
ride, Ag2O, and a ligand.
Initially we optimized the reaction (Scheme 1,Table 1),
with 2-phenyl-1,3,4-oxadiazole (1d)11c and 3-(4-tolyl)pro-
pynoic acid (2b)12 using a palladium catalyst. Various oxi-
dants, ligands, and solvents (Table 1) were examined, con-
sidering the yield of the product, the best result was ob-
tained with PdCl2 (10 mol%), dppp (20 mol%), and Ag2O (2
equiv) in toluene at 80 °C for 10 h (Table 1, entry 4).
With the optimized reaction conditions in hand, several
2-alk-1-ynyl-1,3,4-oxadiazoles 3 were prepared successful-
ly from various 1,3,4-oxadiazoles 1 and α,β-ynoic acids 2
(Scheme 2). Oxadiazoles with different aromatic, heteroar-
omatic, and with electron-donating or -withdrawing sub-
stituted aromatic compounds at the C-2 position under-
went the reaction smoothly. The scope of the reaction was
also examined with various α,β-ynoic acids containing aro-
DOI: 10.1055/s-0036-1588115; Art ID: ss-2016-z0616-op
Abstract For the first time 2-alk-1-ynyl-5-(het)aryl-1,3,4-oxadiazole
derivatives have been synthesized by the decarboxylative cross-cou-
pling of alk-2-ynoic acids with 2-(het)aryl-1,3,4-oxadiazoles, employing
palladium(II) chloride as the catalyst and silver(I) oxide as an oxidant
with 1,3-bis(diphenylphosphanyl)propane as a ligand. Products were
formed in high yields with no byproduct.
Keywords alkynoic acids, 1,3,4-oxadiazole, palladium catalyst, alky-
nylation, cross-coupling, 1,3-bis(diphenylphosphanyl)propane
In recent years, a promising strategy of C–H bond acti-
vation has been extensively utilized for C–C bond forma-
tion, and this is one of the most important topics in organic
chemistry.1 For chemist and biologists, oxadiazole deriva-
tives have become an interesting area of research due to
their wide applications in pharmaceuticals, material sci-
ences, and organic electronics.2 They possess good elec-
tron-transporting, hole-blocking abilities,3 and anticonvul-
sant and antimicrobial activity.4 They also act as amide and
ester bioisosteres.5 Oxadiazole derivatives possess multi-
photon absorbing capacities and optoelectronic properties.6
Substituted alkynes are found to be key building blocks in
organic chemistry, material science, and bioactive natural
products7 and they are versatile synthetic intermediates.8
Thus we realized that 2-alk-1-ynyl-1,3,4-oxadiazoles are bi-
ologically important compounds.
N
N
N
N
PdCl2, oxidant, ligand
solvent, 80 °C, 10 h
O
HOOC
O
3d
1d
2b
Scheme 1 Optimization for Pd-catalyzed C–C cross-coupling of 1,3,4-oxadiazoles with alkynoic acids
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

B
L. M. Reddy et al.
Paper
Synthesis
Table 1 Optimization for Palladium-Catalyzed Cross-Coupling of
2-Phenyl-1,3,4-oxadiazole (1d) and 3-(4-Tolyl)propynoic Acid (2b)
Using Various Oxidants, Ligands, and Solventsa
N
N
N
N
PdCl2, Ag2O, dppp
toluene, 80 °C, 10 h
R2
R1
HOOC
R2
R1
O
O
1
2
3
51–75%
R1 = aryl, heteroaryl
R
Entry
1
Ligand
PPh3
Oxidant
Ag2O
Solvent
toluene
toluene
toluene
toluene
toluene
xylene
Yieldb (%)
31
2 = alkyl, aryl
N
N
N
N
2
dppe
Johnphos
dppp
dppf
Ag2O
71
F
F
O
O
3
Ag2O
trace
75
O
63% (3a)
69% (3b)
75% (3d)
Cl
4
Ag2O
N
N
N
N
5
Ag2O
43
F
O
O
6
dppp
dppp
dppp
dppp
dppp
dppp
Ag2O
35
O
67% (3c)
7
Ag2O
benzene
1,4-dioxane
toluene
toluene
toluene
52
N
O
N
N
N
8
Ag2O
trace
trace
trace
trace
O
O
9
Cu(OTf)2
AgOAc
Cu(OAc)2
69% (3e)
51% (3f)
10
11
N
N
N
N
Cl
O
O
S
a Reaction conditions: 2-phenyl-1,3,4-oxadiazole (1d, 0.5 mmol), 3-(4-
tolyl)propynoic acid (2b, 0.45 mmol), PdCl2 (10 mol%), oxidant (0.9
mmol), ligand (20 mol%), solvent (3 mL).
65% (3g)
57% (3h)
71% (3j)
N
N
N
N
N
b Isolated yield of 3d after column chromatography.
( )6
O
O
64% (3i)
N
N
N
matic, heteroaromatic, and aliphatic substitution at C-3 po-
sition and products were formed in high yields and unre-
acted starting material (1,3,4-oxadiazole) was recovered. All
the products were characterized from the spectral (1H and
13C NMR and MS) data.
In conclusion, we have developed a simple synthesis of
2-alk-1-ynyl-5-(het)aryl-1,3,4-oxadiazoles from alkynoic
acids and 1,3,4-oxadiazoles using PdCl2 as a catalyst.
O
O
O
75% (3k)
59% (3l)
N
N
N
N
O
O
S
S
O
71% (3n)
Cl
68% (3m)
N
N
N
N
O
O
59% (3o)
N
F3C
52% (3p)
60% (3r)
O
N
N
Column chromatography was performed using silica gel 60–120
mesh (Qingdao Marine Chemical, China) and thin-layer chromatogra-
phy (TLC) on Merck Silica Gel 60 F254 plates. NMR spectra: Gemini
200 MHz spectrometer using CDCl3 as solvent and TMS as internal
standard; chemical shifts are expressed as δ values in ppm and cou-
pling constants (J) are given in Hz. ESI-MS: VG-Autospec micromass
instrument. The solvents used were all of AR grade.
N
O
O
N
57% (3q)
N
N
N
O
O
66% (3s)
Abbreviations: 1,2-bis(diphenylphosphanyl)ethane (dppe); 1,3-
Bis(diphenylphosphanyl)propane(dppp); 1,1-bis(diphenylphospha-
nyl)ferrocene (dppf).
Scheme 2 Pd-Catalyzed cross-coupling of 1,3,4-oxadiazoles with alk-
ynoic acids to prepare 2-alk-1-ynyl-1,3,4-oxadiazoles
2-Alk-1-ynyl-5-(het)aryl-1,3,4-oxadiazoles 3a–s; General Proce-
dure
2-(4-Chlorophenyl)-5-[(4-fluorophenyl)ethynyl]-1,3,4-oxadiazole
(3a)
To a 10-mL round-bottom flask PdCl2 (6.7 mg, 10 mol%), dppp (24.7
mg, 20 mol%), Ag2O (208.6 mg, 0.9 mmol), and α,β-ynoic acid 2 (0.45
mmol) and toluene (3 mL) were added under air. To this mixture
1,3,4-oxadiazole 1 (0.5 mmol) was added and the entire mixture was
refluxed at 80 °C for 10 h (TLC monitoring). After completion of the
reaction, the mixture was allowed to cool, quenched by the addition
of H2O, and subsequently extracted with EtOAc (2 × 10 mL). The com-
bined organic extracts were dried (anhyd Na2SO4). Concentration of
the organic layer in vacuo followed by column chromatography (silica
gel) afforded oxadiazole derivatives 3 (Scheme 2).
Yellow solid; yield: 94 mg (0.31 mmol, 63%); Rf = 0.4 (hexane/EtOAc
80:20).
IR: 2225, 1662, 1597, 1536, 1470, 1226 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.02 (d, J = 8.0 Hz, 2 H), 7.70–7.61 (m, 2
H), 7.51 (d, J = 8.0 Hz, 2 H), 7.10 (t, J = 8.0 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 165.5, 163.0 (d, J = 280.0 Hz), 150.6,
138.5, 134.2 (d, J = 4.0 Hz), 129.9, 128.2, 121.7, 116.2 (d, J = 10.0 Hz),
115.9, 96.1, 72.6.
MS (ESI): m/z = 299, 301 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

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L. M. Reddy et al.
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Synthesis
Anal. Calcd for C16H8ClFN2O: C, 64.34; H, 2.70. Found: C, 64.46; H,
2.73.
IR: 2218, 1635, 1602, 1520, 1453, 1253 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.27–8.08 (m, 2 H), 7.91–7.80 (m, 3 H),
7.63 (d, J = 8.0 Hz, 1 H), 7.60–7.49 (m, 6 H).
2-[(4-Fluorophenyl)ethynyl]-5-(2-furyl)-1,3,4-oxadiazole (3b)
13C NMR (50 MHz, CDCl3): δ = 165.0, 150.9, 144.1, 133.9, 133.6, 132.3,
129.9, 129.5, 129.0, 128.4, 128.3, 128.2, 127.1, 123.5, 117.2, 116.0,
97.9, 73.5.
Yellow solid; yield: 87 mg (0.34 mmol, 69%); Rf = 0.35 (hexane/EtOAc
80:20).
IR: 2220, 1606, 1458, 1374, 1228 cm–1
.
MS (ESI): m/z = 319 [M + Na]+.
1H NMR (200 MHz, CDCl3): δ = 7.70–7.61 (m, 3 H), 7.22 (m, 1 H), 7.11
(t, J = 8.0 Hz, 2 H), 6.62 (m, 1 H).
Anal. Calcd for C20H12N2O: C, 81.07; H, 4.08. Found: C, 81.20; H, 4.10.
13C NMR (50 MHz, CDCl3): δ = 165.0, 163.8 (d, J = 280.0 Hz), 152.8,
146.1, 139.2, 134.8 (d, J = 4.0 Hz), 116.4 (d, J = 10.0 Hz), 116.0, 115.9,
112.2, 96.4, 72.9.
2-[(4-Chlorophenyl)ethynyl]-5-phenyl-1,3,4-oxadiazole (3g)
Yellow solid; yield: 91 mg (0.33 mmol, 65%); Rf = 0.35 (hexane/EtOAc
80:20).
MS (ESI): m/z = 255 [M + H]+.
IR: 2224, 1594, 1456, 1282 cm–1
.
Anal. Calcd for C14H7FN2O2: C, 66.14; H, 2.78. Found: C, 66.30; H, 2.75.
1H NMR (200 MHz, CDCl3): δ = 8.11 (d, J = 8.0 Hz, 2 H), 7.63–7.50 (m, 5
H), 7.42 (d, J = 8.0 Hz, 2 H).
2-[(4-Fluorophenyl)ethynyl]-5-(4-methoxyphenyl)-1,3,4-oxadi-
azole (3c)
13C NMR (50 MHz, CDCl3): δ = 165.0, 150.6, 137.1, 133.3, 132.0, 129.1,
127.0, 123.1, 118.7, 114.1, 96.0, 74.2.
MS (ESI): m/z = 281, 283 [M + H]+.
White solid; yield: 98 mg (0.33 mmol, 67%); Rf = 0.30 (hexane/EtOAc
80:20).
Anal. Calcd for C16H9ClN2O: C, 68.46; H, 3.23. Found: C, 68.60; H, 3.25.
IR: 2223, 1609, 1537, 1494, 1262 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.01 (d, J = 8.0 Hz, 2 H), 7.70–7.61 (m, 2
H), 7.11 (t, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 3.90 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 164.1 (d, J = 280.0 Hz), 162.9, 162.2,
150.2, 134.9 (d, J = 4.0 Hz), 131.8, 129.0, 116.3 (d, J = 10.0 Hz), 116.1,
114.9, 96.1, 73.1, 55.6.
2-Phenyl-5-(2-thienylethynyl)-1,3,4-oxadiazole (3h)
Black solid; yield: 71 mg (0.28 mmol, 57%); Rf = 0.4 (hexane/EtOAc
80:20).
IR: 2211, 1544, 1478, 1411, 1211 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.13–8.09 (m, 2 H), 7.59–7.46 (m, 5 H),
7.10 (m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 165.0, 150.9, 135.5, 132.2, 131.0, 129.1,
127.3, 127.1, 126.9, 123.5, 91.0, 77.1.
MS (ESI): m/z = 295 [M + H]+, 317 [M + Na]+.
Anal. Calcd for C17H11FN2O2: C, 69.38; H, 3.77. Found: C, 69.50; H,
3.75.
MS (ESI): m/z = 253 [M + H]+, 275 [M + Na]+.
2-Phenyl-5-(4-tolylethynyl)-1,3,4-oxadiazole (3d)
Anal. Calcd for C14H8N2OS: C, 66.65; H, 3.20. Found: C, 66.52; H, 3.18.
Light yellow solid; yield: 97 mg (0.37 mmol, 75%); Rf = 0.45 (85:15
Hexane/EtOAc).
2-(Non-1-ynyl)-5-phenyl-1,3,4-oxadiazole (3i)
IR: 2215, 1601, 1533, 1476, 1279 cm–1
.
Black solid; yield: 85 mg (0.32 mmol, 64%); Rf = 0.5 (hexane/EtOAc
82:18).
1H NMR (200 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 2 H), 7.56–7.48 (m, 5
H), 7.22 (d, J = 8.0 Hz, 2 H), 2.41 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 164.9, 150.9, 141.2, 132.8, 132.7, 129.3,
129.0, 127.1, 123.4, 116.8, 97.6, 72.8, 21.8.
MS (ESI): m/z = 283 [M + Na]+.
IR: 2223, 1584, 1451, 1250 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.08–7.98 (m, 2 H), 7.58–7.44 (m, 3 H),
2.59 (t, J = 8.0 Hz, 2 H), 1.79–1.70 (m, 2 H), 1.59–1.51 (m, 2 H), 1.48–
1.32 (m, 6 H), 0.96 (t, J = 7.0 Hz, 3 H).
Anal. Calcd for C17H12N2O: C, 78.44; H, 4.65. Found: C, 78.55; H, 4.61.
13C NMR (50 MHz, CDCl3): δ = 161.5, 151.9, 131.9, 129.1, 127.9, 126.8,
98.0, 62.9, 33.2, 30.1, 30.0, 29.9, 22.9, 18.0, 13.2.
MS (ESI): m/z = 291 [M + Na]+.
2-[(2-Methoxyphenyl)ethynyl]-5-phenyl-1,3,4-oxadiazole (3e)
Yellow solid; yield: 95 mg (0.34 mmol, 69%); Rf = 0.4 (hexane/EtOAc
80:20).
Anal. Calcd for C17H20N2O: C, 76.09; H, 7.51. Found: C, 76.21; H, 7.48.
IR: 2219, 1537, 1480, 1275 cm–1
1H NMR (200 MHz, CDCl3): δ = 8.10 (d, J = 8.0 Hz, 2 H), 7.60–7.46 (m, 4
H), 7.39 (t, J = 8.0 Hz, 1 H), 6.99–6.89 (m, 2 H), 3.92 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 164.8, 161.0, 150.9, 134.2, 132.1, 131.9,
129.0, 126.9, 123.2, 120.5, 110.9, 109.1, 94.2, 76.9, 55.8.
.
2-(4-Tolyl)-5-(4-tolylethynyl)-1,3,4-oxadiazole (3j)
Yellow solid; yield: 97 mg (0.35 mmol, 71%); Rf = 0.4 (hexane/EtOAc
80:20).
IR: 2221, 1607, 1538, 1489, 1266 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.98 (d, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.0
Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 2.44 (s, 3 H),
2.40 (s, 3 H).
MS (ESI): m/z = 277 [M + H]+, 299 [M + Na]+.
Anal. Calcd for C17H12N2O2: C, 73.90; H, 4.38. Found: C, 73.78; H, 4.41.
13C NMR (50 MHz, CDCl3): δ = 165.1, 150.5, 143.0, 141.1, 132.1, 129.9,
129.2, 127.0, 120.9, 116.8, 97.3, 72.5, 21.3.
MS (ESI): m/z = 297 [M + Na]+.
2-(2-Naphthylethynyl)-5-phenyl-1,3,4-oxadiazole (3f)
Light yellow solid; yield: 75 mg (0.28 mmol, 51%); Rf = 0.45 (hex-
ane/EtOAc 80:20).
Anal. Calcd For C18H14N2O: C, 78.81; H, 5.14. Found: C, 78.95; H, 5.16.
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L. M. Reddy et al.
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2-(4-Methoxyphenyl)-5-(4-tolylethynyl)-1,3,4-oxadiazole (3k)
1H NMR (200 MHz, CDCl3): 7.94 (d, J = 8.0 Hz, 2 H), 6.98 (d, J = 8.0 Hz,
2 H), 3.85 (s, 3 H), 2.52 (s, 1 H), 2.01–1.63 (m, 4 H), 1.50–1.18 (m, 6 H).
13C NMR (50 MHz, CDCl3): δ = 162.6, 162.5, 151.8, 129.0, 114.5, 114.2,
White solid; yield: 108 mg (0.37 mmol, 75%); Rf = 0.4 (hexane/EtOAc
80:20).
IR: 2220, 1609, 1537, 1492, 1255 cm–1
.
89.0, 68.1, 55.2, 29.9, 28.1, 25.2, 25.0.
MS (ESI): m/z = 283 [M + H]+.
1H NMR (200 MHz, CDCl3): δ = 8.01 (d, J = 8.0 Hz, 2 H), 7.52 (d, J = 8.0
Hz, 2 H), 7.20 (t, J = 8.0 Hz, 2 H), 6.98 (d, J = 8.0 Hz, 2 H), 3.88 (s, 3 H),
2.39 (s, 3 H).
Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43. Found: C, 72.20; H, 6.45.
13C NMR (50 MHz, CDCl3): δ = 165.0, 162.4, 150.8, 141.2, 132.2, 129.6,
129.1, 117.1, 116.0, 114.8, 97.5, 73.0, 55.5, 21.9.
2-(1-Naphthylethynyl)-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadi-
azole (3p)
MS (ESI): m/z = 291 [M + H]+.
Yellow solid; yield: 94 mg (0.26 mmol, 52%); Rf = 0.45 (hexane/EtOAc
65:35).
Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86. Found: C, 74.62; H, 4.90.
IR: 2220, 1534, 1497, 1322, 1292 cm–1
.
2-(1-Naphthylethynyl)-5-(4-tolyl)-1,3,4-oxadiazole (3l)
1H NMR (200 MHz, CDCl3): δ = 8.41 (d, J = 8.0 Hz, 1 H), 8.29 (d, J = 8.0
Hz, 2 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.98–7.85 (m, 2 H), 7.82 (d, J = 8.0 Hz,
2 H), 7.71–7.50 (m, 3 H).
Yellow solid; yield: 91 mg (0.29 mmol, 59%); Rf = 0.45 (hexane/EtOAc
80:20).
13C NMR (50 MHz, CDCl3): δ = 164.0, 152.2, 133.2, 132.8, 132.0, 128.4,
127.9, 127.4, 127.1, 126.1, 125.3, 125.0, 124.1 (q, J = 265.0 Hz), 121.0,
96.2, 75.6.
IR: 2215, 1612, 1532, 1491, 1195 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.40 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.0
Hz, 2 H), 7.98–7.85 (m, 3 H), 7.70–7.48 (m, 3 H), 7.31 (d, J = 8.0 Hz, 2
H), 2.43 (s, 3 H).
MS (ESI): m/z = 365 [M + H]+.
13C NMR (50 MHz, CDCl3): δ = 165.0, 150.6, 143.0, 133.0, 132.9, 132.2,
131.4, 130.0, 128.8, 127.9, 127.1, 127.0, 125.9, 125.2, 120.8, 117.6,
95.5, 77.8, 21.4.
Anal. Calcd for C21H11F3N2O: C, 69.23; H, 3.04. Found: C, 69.35; H,
3.06.
2-(Phenylethynyl)-5-(3-pyridyl)-1,3,4-oxadiazole (3q)
MS (ESI): m/z = 311 [M + H]+.
IR: Brown solid; yield: 70 mg (0.28 mmol, 57%); Rf = 0.35 (hex-
ane/EtOAc 70:30).
Anal. Calcd for C21H14N2O: C, 81.27; H, 4.55. Found: C, 81.44; H, 4.53.
IR: 2218, 1657, 1534, 1277 cm–1
.
2-(4-Chlorophenyl)-5-(2-thienylethynyl)-1,3,4-oxadiazole (3m)
1H NMR (200 MHz, CDCl3): δ = 9.30 (br s, 1 H), 8.79 (m, 1 H), 8.41 (d,
J = 8.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 2 H), 7.52–7.40 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 162.9, 152.9, 151.1, 148.0, 134.3, 132.8,
131.2, 129.0, 124.0, 119.9, 119.7, 98.0, 72.8.
MS (ESI): m/z = 248 [M + H]+.
Black solid; yield: 97 mg (0.34 mmol, 68%); Rf = 0.4 (hexane/EtOAc
80:20).
IR: 2211, 1650, 1599, 1477, 1407, 1211 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.06 (d, J = 8.0 Hz, 2 H), 7.58–7.47 (m, 3
H), 7.01 (dd, J = 2.0, 1.5 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 164.2, 150.9, 138.3, 135.4, 130.8, 129.5,
Anal. Calcd for C15H9N3O: C, 72.87; H, 3.67. Found: C, 72.67; H, 3.69.
128.2, 127.1, 121.2, 119.0, 91.0, 77.2.
2-(3-Pyridyl)-5-(4-tolylethynyl)-1,3,4-oxadiazole (3r)
MS (ESI): m/z = 287, 289 [M + H]+.
Yellow solid; yield: 78 mg (0.30 mmol, 60%); Rf = 0.3 (hexane/EtOAc
65:35).
Anal. Calcd for C14H7ClN2OS: C, 58.64; H, 2.46. Found: C, 58.80; H,
2.44.
IR: 2221, 1586, 1529, 1460, 1273 cm–1
.
2-(4-Methoxyphenyl)-5-(2-thienylethynyl)-1,3,4-oxadiazole (3n)
1H NMR (200 MHz, CDCl3): δ = 9.32 (br s, 1 H), 8.80 (m, 1 H), 8.40 (d,
J = 8.0 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.50 (m, 1 H), 7.24 (d, J = 8.0
Hz, 2 H), 2.41 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 162.5, 152.8, 151.1, 148.2, 141.1, 134.0,
132.2, 129.7, 124.0, 116.9, 98.2, 72.1, 21.9.
Black solid; yield: 100 mg (0.35 mmol, 71%); Rf = 0.35 (hexane/EtOAc
80:20).
IR: 2208, 1607, 1490, 1417, 1256 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.02 (d, J = 8.0 Hz, 2 H), 7.52 (d, J = 1.5
Hz, 1 H), 7.48 (d, J = 2.0 Hz, 1 H), 7.10 (dd, J = 2.0, 1.5 Hz, 1 H), 7.01 (d,
J = 8.0 Hz, 2 H), 3.89 (s, 3 H).
MS (ESI): m/z = 262 [M + H]+.
Anal. Calcd for C16H12N3O: C, 73.55; H, 4.24. Found: C, 73.67; H, 4.21.
13C NMR (50 MHz, CDCl3): δ = 165.0, 162.9, 150.1, 135.4, 130.9, 129.3,
127.9, 119.8, 116.0, 114.4, 90.7, 77.0, 55.2.
2-(2-Furyl)-5-(4-tolylethynyl)-1,3,4-oxadiazole (3s)
MS (ESI): m/z = 283 [M + H]+.
Red solid; yield: 82 mg (0.33 mmol, 66%); Rf = 0.45 (hexane/EtOAc
75:25).
Anal. Calcd for C15H10N2O2S: C, 63.82; H, 3.57. Found: C, 63.97; H,
3.54.
IR: 2214, 1612, 1528, 1338, 1226 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.68 (m, 1 H), 7.53 (d, J = 8.0 Hz, 2 H),
2-(Cyclohexylethynyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole (3o)
7.26–7.18 (m, 3 H), 6.60 (m, 1 H), 2.42 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 157.8, 150.0, 146.1, 141.1, 139.4, 132.6,
Dark green solid; yield: 83 mg (0.29 mmol, 59%); Rf = 0.4 (hex-
ane/EtOAc 75:25).
129.7, 117.0, 114.9, 112.8, 108.1, 72.5, 21.9.
IR: 1610, 1497, 1456, 1258 cm–1
.
MS (ESI): m/z = 251 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

E
L. M. Reddy et al.
Paper
Synthesis
Anal. Calcd for C15H10N2O2: C, 71.99; H, 4.03. Found: C, 71.80; H, 4.05.
(8) Sonogashira, K. Comprehensive Organic Synthesis; Vol. 3; Trost,
B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, 521.
(9) (a) Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon, J. H.; Jung, H. M.;
Lee, S. Org. Lett. 2008, 10, 945. (b) Kim, H.; Lee, P. H. Adv. Synth.
Catal. 2009, 351, 2827. (c) Moon, J.; Jang, M.; Lee, S. J. Org. Chem.
2009, 74, 1403. (d) Zhang, W.-W.; Zhang, X.-G.; Li, J.-H. J. Org.
Chem. 2010, 75, 5259. (e) Park, K.; Bae, G.; Moon, J.; Choe, J.;
Song, K. H.; Lee, S. J. Org. Chem. 2010, 75, 6244. (f) Zhao, D.-B.;
Gao, C.; Su, X.-Y.; He, Y.-Q.; You, J.-S.; Xue, Y. Chem. Commun.
2010, 46, 9049. (g) Jiao, N. Tetrahedron Lett. 2010, 51, 1287.
(h) Pan, D.-L.; Zhang, C.; Ding, S.-T.; Jiao, N. Eur. J. Org. Chem.
2011, 4751. (i) Li, T.-Y.; Qu, X.-M.; Zhu, Y.; Sun, P.; Yang, H.-L.;
Shan, Y.-Q.; Zhang, H.-X.; Liu, D.-F.; Zhang, X.; Mao, J.-C. Adv.
Synth. Catal. 2011, 353, 2731. (j) Rodríguez, N.; Goossen, L. J.
Chem. Soc. Rev. 2011, 40, 5030. (k) Li, T.-Y.; Sun, P.; Yang, H.-L.;
Zhu, Y.; Yan, H.; Lu, L.-H.; Mao, J.-C. Tetrahedron 2012, 68, 6413.
(l) Tartaggia, S.; Lucchi, O. D.; Goossen, L. J. Eur. J. Org. Chem.
2012, 1431. (m) Li, X. L.; Yang, F.; Wu, Y. J. Org. Chem. 2013, 78,
4543. (n) Reddy, P. V.; Srinivas, P.; Annapurna, M.; Bhargava, S.;
Wagler, J.; Mirzadeh, N.; Kantam, M. L. Adv. Synth. Catal. 2013,
355, 705. (o) Fu, Y. J. Org. Chem. 2013, 78, 4551.
(10) (a) Zhao, B. Org. Biomol. Chem. 2012, 10, 7108. (b) Park, K.; Lee,
S. RSC Adv. 2013, 3, 14165. (c) Kim, J.; Kang, D.; Yoo, E. J.; Lee, P.
H. Eur. J. Org. Chem. 2013, 7902.
(11) (a) Kawano, T.; Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M.
J. Org. Chem. 2010, 75, 1764. (b) Kitahara, M.; Hirano, K.;
Tsurugi, H.; Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 1772.
(c) Chinna Reddy, G.; Balasubramanyam, P.; Salvanna, N.; Das,
B. Eur. J. Org. Chem. 2012, 471. (d) Salvanna, N.; Das, B. Synlett
2014, 25, 2033. (e) Theunissen, C.; Evano, G. Org. Lett. 2014, 16,
4488.
Acknowledgement
The authors thank CSIR and UGC, New Delhi for financial assistance.
References
(1) (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
(b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (c) Johansson, C. C. C.; Colacot, T. J. Angew. Chem. Int.
Ed. 2010, 49, 676.
(2) (a) Mitschke, U.; Bauerle, 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.
(3) Singh, S.; Sharma, L. K.; Saraswat, A.; Siddiqui, I. R.; Kheri, H. K.;
Singh, R. K. P. RSC Adv. 2013, 3, 4237.
(4) (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. Chem. Sin. 2010,
1, 118; http://pelagiaresearchlibrary.com/der-chemica-sinica/
index.html.
(5) Leung, D.; Du, W.; Hardouin, C.; Cheng, H.; Hwang, I.; Cravatt, B.
F.; Boger, D. L. Bioorg. Med. Chem. Lett. 2005, 15, 1423.
(6) (a) He, G. S.; Tan, L.-S.; Zheng, Q.; Prasad, P. N. Chem. Rev. 2008,
108, 1245. (b) Guin, S.; Ghosh, T.; Rout, S. K.; Banarjee, A.; Patel,
B. K. Org. Lett. 2011, 13, 5976.
(7) (a) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem. Int.
Ed. 2000, 39, 2632. (b) Sonogashira, K. J. Organomet. Chem.
2002, 653, 46. (c) Tykwinski, R. R. Angew. Chem. Int. Ed. 2003, 42,
1566; Angew. Chem. 2003, 115, 1604. (d) Jutand, A. Pure Appl.
Chem. 2004, 76, 565.
(12) (a) Park, K.; Palani, T.; Pyo, A.; Lee, S. Tetrahedron Lett. 2012, 53,
733. (b) Park, K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H.; Lee, S.
J. Org. Chem. 2010, 75, 6244.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E