Synthesis of 2-alkynyl 1,3,4-oxadiazoles by palladium-catalyzed cross- coupling reaction 1

Article abstract of DOI:10.1055/s-0034-1378361

Several 2-alkynyl 1,3,4-oxadiazoles have been synthesized efficiently by employing palladium-catalyzed cross-coupling under Sonogashira reaction conditions. This reaction has been applied for the first time for the preparation of oxadiazole derivatives. T

Full text of DOI:10.1055/s-0034-1378361

LETTER
▌2033
lSetyternthesis of 2-Alkynyl 1,3,4-Oxadiazoles by Palladium-Catalyzed Cross-
Coupling Reaction1
2-Alkynyl 1,3,4-Oxadiazoles
N. Salvanna, Biswanath Das*
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: biswanathdas@yahoo.com
Received: 15.04.2014; Accepted after revision: 30.05.2014
PdCl2(PPh3)2
(5 mol%)
Abstract: Several 2-alkynyl 1,3,4-oxadiazoles have been synthe-
sized efficiently by employing palladium-catalyzed cross-coupling
under Sonogashira reaction conditions. This reaction has been ap-
plied for the first time for the preparation of oxadiazole derivatives.
The products were formed in high yields and no side products were
detected.
N
N
O
N
N
R2
R2
Br
+
CuI (10 mol%)
Et3N (2 equiv)
DMF, 60 °C
6–16 h
O
R1
R1
1
2
3
78–92%
R
R
1 = aryl, heteroaryl
2 = aryl, aliphatic
Key words: 1,3,4-oxadiazole, Sonogashira coupling, palladium-
catalyzed reaction, copper(I) iodide, alkynylation
Scheme 1 Palladium-catalyzed C–C cross-coupling
Initially we optimized the reaction conditions with 2-bro-
mo-5-phenyl-1,3,4-oxadiazole (1a) and 2-(4-methylphe-
nyl)acetylene (2a) using various amounts of different
palladium catalysts and CuI (Table 1). Different bases and
solvents were also used. In addition, the temperature and
the time of the reaction were varied. Considering the yield
of the reaction the best result was obtained when
PdCl2(PPh3)2 (5mol%), CuI (10 mol%), and Et3N (2
equiv) were used in DMF at 60 °C for six hours (Table 1,
entry 1). In the absence of CuI the yield was low (Table 1,
entry 6). When the reaction was conducted with other bases
(such as Cs2CO3, i-PrNH; Table 1, entries 7 and 8) and
other solvents (such as THF, DMSO, dioxane; Table 1,
entries 2, 4, and 5) the yield was also low. On increasing
the amount of base (Et3N) no significant change in yield
was observed (Table 1, entry 9). The reaction was also
carried out at room temperature but the reaction time in-
creased and the yield was lower (Table 1, entry 10).
Oxadiazole derivatives are highly important in pharma-
ceutical and material sciences. They are used as antimi-
crobial and anticonvulsant agents.2 They also act as amide
and ester bioisosteres.3 In addition, substituted oxadia-
zoles possess multiphoton-absorbing capacities and opto-
electronic properties.4 They are also known to exhibit
good electron-transporting and hole-blocking abilities5
and consequently find application in the development of
organic electronics.6 Herein we report the first application
of the Sonogashira reaction7 for the efficient synthesis of
2-alkynyl 1,3,4-oxadiazoles.
Substituted alkynes are a common unit in natural products
and bioactive compounds and are found to be an impor-
tant feature in various bioactive substances, such as en-
dyne antibiotics.8 The alkyne moiety can also extend the
conjugation of aryl and heteroaryl rings with which it is
attached. Thus we realized that 2-alkynyl 1,3,4-oxadia-
zoles may have bioactivity as well as potential for use in
organic materials chemistry.
In continuation of our work9 on the synthesis of substitut-
ed oxadiazoles we discovered that 2-bromo-1,3,4-oxadia-
zoles (1; readily be prepared from 1,3,4-oxadiazoles10)
can be subjected to palladium-catalyzed cross-coupling
with terminal alkynes under Sonogashira reaction
conditions7 to prepare 2-alkynyl 1,3,4-oxadiazoles
(Scheme 1).
It was also observed that – with other terminal acetylenes
other than 2-(4-methylphenyl)acetylene – longer times
were required (Table 2). The conversion also did not pro-
ceed smoothly with 2-chloro-1,3,4-oxadiazoles, requiring
longer reaction times and resulting in lower yields.
After optimization of the reaction conditions (Table 1)
several 2-alkynyl-1,3,4-oxadiazoles (3) were prepared
successfully from various 2-bromo-1,3,4-oxadiazoles 1
and terminal alkynes 2 (Table 2). The bromooxadiazoles
contained different aromatic moieties at C-5 possessing
electron-donating as well as electron-withdrawing groups
as well as oxygen and nitrogen heterocycles. The terminal
alkynes also contained aromatic and heteroaromatic rings
at C-2 and even an alkyne with a long aliphatic chain un-
derwent the transformation smoothly (Table 2, entry 6).
The products were formed in high yields within 6–16
hours. All the products were characterized from their
spectroscopic data and were compared to known com-
pounds.9 No side reaction including alkyne homocoupling
could be observed.
Alkynylation of heterocyclic-based halides using Sono-
gashira reaction conditions has been frequently employed
for the preparation of various novel systems.11 However,
to our knowledge, this reaction has not yet been applied
for the generation of oxadiazolyl alkynes (Scheme 1).
SYNLETT 2014, 25, 2033–2035
Advanced online publication: 16.07.2014
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9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378361; Art ID: st-2014-d0316-l
© Georg Thieme Verlag Stuttgart · New York

2034
N. Salvanna, B. Das
LETTER
Table 1 Optimization of Reaction Conditions for the Cross-Coupling of 2-Bromo-5-phenyl-1,3,4-oxadiazole (1a) with 2-(4-Methylphe-
nyl)acetylene (2a) Using Different Metal Catalysts and Various Basesa
N
PdCl2(PPh3)2 (5 mol%)
N
O
N
N
Br
+
CuI (10 mol%)
Et3N (2 equiv)
solvent, 60–120 °C
6–36 h
O
Ph
Ph
1a
2a
3aa
Entry
Catalyst
Base
Solvent
Temp (°C)
Time (h)
Yield (%)b
1
2
PdCl2(PPh3)2, CuI
PdCl2(PPh3)2, CuI
PdCl2(PPh3)2, CuI
PdCl2(PPh3)2, CuI
PdCl2(PPh3)2, CuI
PdCl2(PPh3)2
Et3N
DMF
THF
60
60
6
10
24
16
12
36
24
24
6
92
58
68
62
55
15
54
66
92d
40c
Et3N
3
i-Pr2NH
Et3N
DMF
DMSO
dioxane
DMF
DMF
DMF
DMF
DMF
120
60
4
5
Et3N
60
6
Et3N
60
7
PdCl2(PPh3)2, CuI
PdCl2(PPh3)2, CuI
PdCl2(PPh3)2, CuI
PdCl2(PPh3)2, CuI
Cs2CO3
i-Pr2NH
Et3N
120
120
60
8
9
10
Et3N
27
24
a Reaction conditions: 2-bromo-5-phenyl-1,3,4-oxadiazole 1a (0.7 mmol), 2 (4-methylphenyl) acetylene 2 (1.0 mmol), (PdCl2(PPh3)2 (5 mol%),
CuI (10 mol%), base (2.0 equiv), 60–120 °C, 6–36 h, solvent (3 mL).
b Isolated yield of 3 after column chromatography.
c Reaction was carried out at r.t. (27 °C).
d Base (4.0 equiv).
2-Phenyl-5-(thiophen-2-ylethynyl)-1,3,4-oxadiazole (3af)
IR (neat): 2211, 1544, 1478, 1411, 1211 cm–1. 1H NMR (200 MHz,
CDCl3): δ = 8.13–8.09 (2 H, m), 7.59–7.46 (5 H, m), 7.10 (1 H, m).
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; ESI-MS: m/z 253
[M + H]+, 275 [M + Na]+. ESI-HRMS: m/z calcd for C14H8N2OSNa
[M + Na]+: 275.0255; found: 275.0250.
In conclusion, we have successfully applied the Sono-
gashira reaction for the first time for the synthesis of a se-
ries of 2-alkynyl 1,3,4-oxadiazoles. The products were
formed under mild reaction conditions and in high yield.
General Experimental Procedure for the Alkynylation of 2-Bromo
1,3,4-Oxadiazoles with Terminal Alkynes
2-(Non-1-ynyl)-5-phenyl-1,3,4-oxadiazole (3ag)
IR (neat): 2223, 1584, 1451, 1250 cm–1. 1H NMR (200 MHz,
CDCl3): δ = 8.08–7.98 (2 H, m), 7.58–7.44 (3 H, m), 2.59 (2 H, t,
J = 8.0 Hz), 1.79–1.70 (2 H, m), 1.59–1.51 (2 H, m), 1.48–1.32 (6
H, m), 0.96 (3 H, t, J = 7.0 Hz). 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. ESI-MS: m/z 291 [M + Na]+. ESI-
HRMS: m/z calcd for C17H20N2ONa [M + Na]+: 291.0689; found:
291.0685.
In a 10 mL round-bottom flask under N2 atmosphere, 2-bromo-
1,3,4-oxadiazole (0.7 mmol), alkyne (1.0 mmol), PdCl2(PPh3)2 (5
mol%), CuI (10 mol%), and Et3N (2.0 equiv) in anhydrous DMF
(2.0 mL) were combined. The reaction mixture was stirred at 60 °C
for 6–16 h, and progress of reaction was monitored by TLC. After
the consumption of the starting materials, the reaction mixture was
allowed to cool, and subsequently extracted with Et2O (2 × 15 mL).
The combined organic extracts were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo followed by flash chromatogra-
phy on silica to afford the corresponding 2-alkynyl-1,3,4-oxadia-
zole in good yield.
2-(Naphthalen-1-ylethynyl)-5-p-tolyl-1,3,4-oxadiazole (3be)
IR (neat): 2215, 1612, 1532, 1491, 1195 cm–1. 1H NMR (200 MHz,
CDCl3): δ = 8.40 (1 H, d, J = 8.0 Hz), 8.04 (2 H, d, J = 8.0 Hz), 7.98–
7.85 (3 H, m), 7.70–7.48 (3 H, m), 7.31 (2 H, d, J = 8.0 Hz), 2.43 (3
H, s). 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. ESI-MS: m/z = 311 [M + H]+. ESI-
HRMS: m/z calcd for C21H15N2O [M + H]+ 311.1184; found:
311.1178.
Selected Spectroscopic Data
2-Phenyl-5-(p-tolylethynyl)-1,3,4-oxadiazole (3ab)
IR (neat): 2215, 1601, 1533, 1476, 1279 cm–1. 1H NMR (200 MHz,
CDCl3): δ = 8.09 (2 H, d, J = 8.0 Hz), 7.56–7.48 (5 H, m), 7.22 (2
H, d, J = 8.0 Hz), 2.41 (3 H, s). 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. ESI-MS: m/z = 283 [M + Na]+. ESI-HRMS: m/z
calcd for C17H12N2ONa [M + Na]+: 283.0847; found: 283.0849.
Acknowledgment
The authors thank UGC and CSIR, New Delhi for financial assi-
stance.
Synlett 2014, 25, 2033–2035
© Georg Thieme Verlag Stuttgart · New York

LETTER
2-Alkynyl 1,3,4-Oxadiazoles
2035
References and Notes
Table 2 Palladium-Catalyzed Cross-Coupling of Various Terminal
Alkynes with 2-Bromo-5-aryl-1,3,4-oxadiazolea
(1) Part 236 in the series ‘Studies on novel synthetic
methodologies’.
PdCl2(PPh3)2
(5 mol%)
N
N
O
N
N
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Br
+
R2
R2
CuI (10 mol%)
Et3N (2 equiv)
DMF, 60 °C
6–16 h
O
R1
R1
1
2
3
(3) Leung, D.; Du, W.; Hardouin, C.; Cheng, H.; Hwang, I.;
Cravatt, B. F.; Boger, D. L. Bioorg. Med. Chem. Lett. 2005,
15, 1423.
Entry R1
R2
Time (h) Yield (%)b
1
2
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
2b 4-MeC6H4
2c 4-ClC6H4
2d 4-FC6H4
2e 2-naphthyl
2f 2-thienyl
2g heptyl
6
10
12
14
8
3ab 92
3ac 80
3ad 82
3ae 78
3af 84
3ag 80
3ai 84
3bb 87
3be 90
3cb 90
3cd 82
3cf 84
3ch 78
3dd 85
3df 86
3ee 80
3fb 88
3fd 84
3ga 80
3gb 78
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2008, 108, 1245. (b) Guin, S.; Ghosh, T.; Rout, S. K.;
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3
4
5
6
16
8
7
2ai 2-MeOC6H4
2b 4-MeC6H4
2e 2-naphthyl
2b 4-MeC6H4
2d 4-FC6H4
2f 2-thienyl
2h cyclohexyl
2d 4-FC6H4
2f 2-thienyl
2e 2-naphthyl
2b 4-MeC6H4
2d 4-FC6H4
2a Ph
8
1b 4-MeC6H4
1b 4-MeC6H4
7
9
10
8
10
11
12
13
14
15
16
17
18
19
20
1c 4-MeOC6H4
1c 4-MeOC6H4
1c 4-OMeC6H4
1c 4-MeOC6H4
1d 4-ClC6H4
1d 4-ClC6H4
1e 4-F3CC6H4
1f 2-furyl
14
12
16
12
14
10
8
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1f 2-furyl
10
10
8
1g 2-nicotyl
1g 2-nicotyl
2b 4-MeC6H4
(10) Boga, C.; Del Vecchio, E.; Forlani, L.; Todesco, P. E.
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a Reaction conditions: 2-bromo-5-aryl 1,3,4-oxadiazole 1 (0.7 mmol),
alkyne 2 (1.0 mmol), (PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), base
(2.0 equiv), 60 °C, 6–16 h, DMF (3 mL).
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2003, 42, 5993. (b) Doucet, H.; Hierso, J. C. Angew. Chem.
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b Isolated yield of 3 after column chromatography.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2033–2035

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