Copper-mediated C-H activation of 1,3,4-oxadiazoles with 1,1-dibromo-1-alkenes using PEG-400 as a solvent medium: Distinct approach for the alkynylation of 1,3,4-oxadiazoles

Article abstract of DOI:10.1002/ejoc.201101542

The direct C-H alkynylation of 1,3,4-oxadiazoles with 1,1-dibromo-1-alkenes has been accomplished by using a combination of CuBr/LiOtBu in PEG-400 (a green solvent) at 80 °C. The products were formed in high yields (73-86%) in 2 h. No additional ligand or volatile solvent was required and the conversion was ecofriendly. The direct C-H alkynylation of 1,3,4-oxadiazoles with 1,1-dibromo-1-alkenes has been accomplished by using a combination of CuBr/LiOtBu in PEG-400 (a green solvent) at 80 °C. The products were formed in high yields (73-86%) in 2 h. No additional ligand or volatile solvent was required and the conversion was ecofriendly. Copyright

Full text of DOI:10.1002/ejoc.201101542

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101542
Copper-Mediated C–H Activation of 1,3,4-Oxadiazoles with 1,1-Dibromo-1-
alkenes Using PEG-400 as a Solvent Medium: Distinct Approach for the
Alkynylation of 1,3,4-Oxadiazoles[‡]
Gandolla Chinna Reddy,[a] Penagaluri Balasubramanyam,[a] N. Salvanna,[a] and
Biswanath Das*[a]
Keywords: C-H activation / Heterocycles / Alkenes / Copper / Alkynes
The direct C–H alkynylation of 1,3,4-oxadiazoles with 1,1-
The products were formed in high yields (73–86%) in 2 h.
dibromo-1-alkenes has been accomplished by using a combi- No additional ligand or volatile solvent was required and the
nation of CuBr/LiOtBu in PEG-400 (a green solvent) at 80 °C.
conversion was ecofriendly.
efficient copper-catalyzed conversion of 1,3,4-oxadiazoles
by employing gem-dibromoalkenes for the preparation of
alkynylated 1,3,4-oxadiazoles.
Introduction
Oxadiazole derivatives exhibit various important bio-
logical properties including antimicrobial and anticonvul-
sant activities.[1] They are also known to act as ester and
amide bioisosters.[2] Certain oxadiazole derivatives have
been applied in the development of organic electronics.[3]
Consequently, the preparation of these compounds is of
considerable importance in organic synthesis.
Results and Discussion
In continuation of our work[9] on the development of
useful synthetic methodologies, we observed that 1,3,4-oxa-
diazoles, when treated with 1,1-dibromo-1-alkenes by using
CuBr and LiOtBu in polyethylene glycol (PEG-400) at
80 °C, afforded the corresponding 2-alkynyl derivatives in
2 h (Scheme 1).
The metal-catalyzed direct transformation of C–H bonds
into C–C bonds in arenes and heteroarenes has recently
been identified as an important method for the preparation
of oxadiazole derivatives.[4] Various metal catalysts such as
palladium, ruthenium, and rhodium have been employed to
carry out these transformations. However, copper catalysts
have not been employed so much for this purpose, although
their availability is greater and they are less expensive. Their
activity is also prominent. Recently, these catalysts have
been used for the C–H activation of several arenes and
heteroarenes.[5] However, to the best of our knowledge, the
copper-mediated C–H activation of 1,3,4-oxadiazoles by
using gem-dibromoalkenes has not yet been reported, al-
though direct alkynylations with alkynyl bromides[4h] or ter-
minal alkynes[6] are known. Other copper-catalyzed trans-
formations of oxadiazoles have also recently been discov-
ered.[4b,7] The synthetic applications of gem-dibromoethenes
as an alkynyl donor are also known.[8] Here we disclose an
Scheme 1. Copper-catalyzed C–C cross coupling.
Initially, 2-phenyl-1,3,4-oxadiazole (1a) was treated with
1-(2,2-dibromovinyl)-4-methylbenzene (2a) for the optimi-
zation of the reaction conditions. The reaction was carried
out with various copper compounds and different bases and
solvents (Table 1).
The conversion was found to be most effective when
CuBr (10 mol-%) and LiOtBu (2.0 equiv.) were used in
PEG-400 at 80 °C. The yield was 82% after 2 h. When the
temperature was raised to 120 °C, the yield remained un-
changed, but at room temperature the yield was low (39%).
The catalytic activities of CuBr2, CuCl, and CuI were weak.
Instead of PEG-400, when CH2Cl2 and CH3CN were used
[‡] Studies on Novel Synthetic Methodologies, 231.
Part 230: B. Das, N. Bhunia, M. Lingaiah, Synthesis, 2011,
3471.
[a] Organic Division-I, Indian Institute of Chemical Technology,
Uppal Road, Hyderabad-500007, India
Fax: +91-40 27160512
E-mail: biswanathdas@yahoo.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101542.
Eur. J. Org. Chem. 2012, 471–474
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G. C. Reddy, P. Balasubramanyam, N. Salvanna, B. Das
SHORT COMMUNICATION
Table 1. Optimization of the C–H activation of 2-phenyl-1,3,4-
oxadiazole with 1-(2,2-dibromovinyl)-4-methylbenzene by using
PEG-400 as the solvent.[a]
Table 2. Copper-mediated direct cross-coupling of 2-phenyl-1,3,4-
oxadiazole with different 1,1-dibromo-1-alkenes by using PEG-400
as the solvent.[a]
Entry
Cu source
Base
T [°C]
Yield [%][b]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuBr
CuBr
CuBr
CuBr
K2CO3
K3PO4
LiOtBu
Cs2CO3
LiOtBu
LiOtBu
K3PO4
LiOtBu
Cs2CO3
LiOtBu
K3PO4
LiOtBu
LiOtBu
LiOtBu
LiOtBu
80
80
80
80
120
80
80
120
80
80
80
80
80
80
r.t.
45
54
69
47
69
82
59
82
51
35
26
48
51
57
39[c]
9
10
11
12
13
14
15
Cu(PPh3)Br
Cu(PPh3)Br
CuBr2
CuCl
Cu2O
CuBr
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Cu source
(10 mol-%), base (1.0 equiv.), PEG-400 at 80 °C over 2 h. [b] Iso-
lated yield of 3aa after column chromatography. [c] Room tempera-
ture = 27 °C.
as the solvent the reaction did not proceed. Among the
bases, LiOtBu was found to be the most efficient, and with
other bases the yields were low.
Following the standardization of the above reaction, a
series of alkynylated derivatives of 2-phenyl-1,3,4-oxadi-
azoles were prepared by using different 1,1-dibromo-1-alk-
enes (Table 2). Aromatic, heteroaromatic, and aliphatic alk-
enes underwent the conversion smoothly. The products
were formed in high yields (73–86%). 1,1-Dibromo-2-naph-
thylethylene also afforded desired alkyne 3af (Table 2, En-
try 6) in an impressive yield of 81%.
[a] Reaction conditions: 1a (0.5 mmol),
(10 mol-%), LiOtBu (2.0 equiv.), PEG-400(2 mL) at 80 °C over 2 h.
[b] Isolated yield of 3 after column chromatography.
2 (0.6 mmol), CuBr
The present copper-mediated direct cross-coupling reac-
tion was carried out by using various 2-aryl-1,3,4-oxadi-
azoles and different 1,1-dibromo-1-alkenes (Table 3). The
With an understanding of copper-catalyzed cross-cou-
aryl group of the oxadiazoles contained both aromatic and pling reactions,[12] a plausible mechanism for the present
heteroaromatic moieties. The aromatic moiety possessed conversion is given in Scheme 2. The reaction medium,
electron-donating as well as electron-withdrawing groups, polyethylene glycol, acts as a ligand[13] to form species A.
whereas the heteroaromatic moiety comprised oxygen and The mechanism involves (heteroaryl) CuI intermediate I
nitrogen heterocycles. The 1,1-dibromo-1-alkenes also con- and CuIII complex II to form alkynylated product 3.
tained both aromatic and aliphatic groups. Thus, the pres-
ent conversion has versatile scope for the preparation of rived from the 1,1-dibromo-1-alkenes interact with I to
various alkynylated oxadiazole derivatives. form complex III, which produces alkynylated derivative 3
PEG-400 was used here as a reaction medium.[10] In re- (Scheme 3).
In an alternative mechanism, the alkynyl bromides de-
cent years, chemists have tended to avoid volatile organic
The present conversion took place spontaneously and no
solvents, especially chlorinated solvents, which create envi- intermediate could be isolated. However, when we treated a
ronmental problems. Polyethylene glycol has now been in- 1,3,4-oxadiazole with a bromoacetylene under similar reac-
troduced as a green solvent system.[11] It is less expensive, tion conditions; the alkynylated product was produced in
recyclable, and miscible with different organic solvents. This high yield (Scheme 4). Thus, we feel that the second mecha-
solvent medium has successfully been utilized here for alk- nism (Scheme 3) is more favorable for the present conver-
ynylation of oxadiazoles.
sion.
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Eur. J. Org. Chem. 2012, 471–474

Copper-Mediated C–H Activation of 1,3,4-Oxadiazoles
Table 3. Copper-mediated direct cross-coupling of various 1,3,4-
oxadiazole with different 1,1-dibromo-1-alkenes by using PEG-400
as the solvent.[a]
Scheme 2.
Scheme 3.
Scheme 4.
Conclusions
In conclusion we have developed an efficient copper-me-
diated, green method for the alkynylation of 1,3,4-oxadi-
azoles by using PEG-400 as the solvent medium. Costly Pd-
based catalysts have been avoided. The mild reaction condi-
tions, operational simplicity, ligand- and volatile-solvent-
free conversion, application of a nontoxic and recyclable
medium, high yields, and rapid formation of the products
are the notable advantages of this method.
[a] Reaction conditions: 1 (0.5 mmol), 1,1-dibromo-1-alkene 2
(0.6 mmol), CuBr (10 mol-%), LiOtBu (2.0 equiv.), PEG-400 at
80 °C over 2 h. [b] Isolated yield of 3 after column chromatography.
Eur. J. Org. Chem. 2012, 471–474
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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473

G. C. Reddy, P. Balasubramanyam, N. Salvanna, B. Das
SHORT COMMUNICATION
Besselievre, S. Piguel, F. Mahuteau-Betzer, D. S. Grierson, Org.
Lett. 2008, 10, 4029; e) J. Koubachi, S. El Kazzouli, S. Berte-
ina-Raboin, K. Mouaddib, G. Guillaumet, Synthesis 2008,
2537; f) C. Verrier, C. Hoarau, F. Marsais, Org. Biomol. Chem.
2009, 7, 647; g) I. V. Seregin, V. Ryabova, V. Gevorgyan, J. Am.
Chem. Soc. 2007, 129, 7742; h) T. Kawano, N. Matsuyama, K.
Hirano, T. Satoh, M. Miura, J. Org. Chem. 2010, 75, 1764; i)
F. Monnier, F. Turtaut, L. Duroure, M. Taillefer, Org. Lett.
2008, 10, 3203.
Experimental Section
General Experimental Procedure for the Alkynylation of 1,3,4-Oxa-
diazoles with 1,1-Dibromo-1-alkenes: A 10-mL round-bottomed
flask was loaded with CuBr (7 mg, 0.05 mmol), LiOtBu (80 mg,
1.0 mmol), 1,1-dibromo-1-alkene (0.60 mmol), and the 1,3,4-oxadi-
azole (0.50 mmol) in PEG-400 (2.0 mL). The reaction mixture was
stirred at 80 °C for 2 h. The progress of the reaction was monitored
by TLC. After the consumption of the starting materials, the reac-
tion mixture was allowed to cool and subsequently extracted with
diethyl ether (4ϫ10 mL). The combined organic extracts were
dried with anhydrous Na2SO4. Concentration of the material in
vacuo followed by flash chromatography on silica gel column af-
forded the 2-alkynyl-1,3,4-oxadiazole in good yield.
[5] a) H.-Q. Do, R. M. K. Khan, O. Daugulis, J. Am. Chem. Soc.
2008, 130, 15185; b) H.-Q. Do, O. Daugulis, J. Am. Chem. Soc.
2008, 130, 1128; c) J. J. Mousseau, J. A. Bull, A. B. Charette,
Angew. Chem. 2010, 122, 1133; Angew. Chem. Int. Ed. 2010,
49, 1115; d) X. Chen, X.-H. Hao, C. E. Goodhue, J.-Q. Yu, J.
Am. Chem. Soc. 2006, 128, 6790.
[6] M. Kitahara, K. Hirano, H. Tsurugi, T. Satoh, M. Miura,
Chem. Eur. J. 2010, 16, 1772.
2-Phenyl-5-(p-tolylethynyl)-1,3,4-oxadiazole (3aa): IR: ν = 2215,
˜
1601, 1533, 1476, 1279 cm–1. 1H NMR (200 MHz, CDCl3): δ =
8.09 (d, 2 H, J = 8.0 Hz), 7.56–7.48 (m, 5 H), 7.22 (d, J = 8.0 Hz,
2 H), 2.41 (s, 3 H) ppm. 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 ppm. MS (ESI): m/z = 283 [M + Na]+. HRMS (ESI):
calcd. for C17H12N2ONa [M + Na]+ 283.0847; found 283.0849.
[7] a) T. Kawano, K. Hirano, T. Satoh, M. Miura, J. Am. Chem.
Soc. 2010, 132, 6900; b) N. Matsuda, K. Hirano, T. Satoh, M.
Miura, Org. Lett. 2011, 13, 2860; c) H. Hachiya, K. Hirano, T.
Satoh, M. Miura, Org. Lett. 2011, 13, 3076.
[8] a) S. G. Newman, V. Aureggi, C. S. Bryan, M. Lautens, Chem.
Commun. 2009, 5236; b) H. Hachiya, K. Hirano, T. Satoh, M.
Miura, Angew. Chem. 2009, 121, 4445; Angew. Chem. Int. Ed.
2009, 48, 4381; c) A. Coste, F. Couty, G. Evano, Org. Lett.
2009, 11, 4454; d) . J. Yuen, Y.-Q. Fang, M. Lautens, Org. Lett.
2006, 8, 653; e) P. B. Berciano, S. Lebriquier, F. Besselievre, S.
Piguel, Org. Lett. 2010, 12, 4038.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, spectral data, and copies of the 1H NMR
and 13C NMR spectra of all compounds.
[9] a) B. Das, G. C. Reddy, P. Balasubramanyam, N. Salvanna,
Synthesis 2011, 816; b) B. Das, N. Salvanna, G. C. Reddy, P.
Balasubramanyam, Tetrahedron Lett. 2011, 52, 6497.
[10] a) T. J. Dickerson, N. N. Reed, K. D. Janda, Chem. Rev. 2002,
102, 3325; b) S. Chandrasekhar, S. S. Narasimhulu, N. R. Sul-
tana, N. R. Reddy, Chem. Commun. 2003, 1716; c) B. Das, P.
Balasubramanyam, G. C. Reddy, N. Salvanna, Helv. Chim.
Acta 2011, 94.
Acknowledgments
The authors thank the Council of Scientific and Industrial Re-
search (CSIR) and the University Grants Commission (UGC),
New Delhi for financial assistance.
[11] a) J. Chen, S. K. Spear, J. G. Huddleston, R. D. Rogers, Green
Chem. 2005, 7, 64; b) R. Kumar, P. Chaudary, S. Nimesh, R.
Chandra, Green Chem. 2006, 8, 356.
[1] a) S. A. F. Rostom, M. A. Shalaby, M. A. El-Demellawy, Eur.
J. Med. Chem. 2003, 38, 959; b) G. S. He, L. S. Tan, Q. Zheng,
P. N. Prasad, Chem. Rev. 2008, 108, 1245; c) K. K. Jha, A. Sa- [12] a) J. Hassan, M. Sevignou, C. Gozzi, E. Schulz, M. Lemaise,
mad, Y. Kumar, M. Shaharyar, R. L. Khosa, J. Jain, V. Kumar,
P. Sing, Eur. J. Med. Chem. 2010, 45, 4963; d) P. Singh, P. K.
Jangra, Der. Chem. Sinica 2010, 1, 118.
Chem. Rev. 2002, 102, 1359; b) S. V. Ley, A. W. Thomas, An-
gew. Chem. 2003, 115, 5558; Angew. Chem. Int. Ed. 2003, 42,
5400; c) L. M. Huffman, S. S. Stahl, J. Am. Chem. Soc. 2008,
130, 9196; d) R. J. Phipps, M. J. Gaunt, Science 2009, 323,
1593; e) T. Kawano, T. Yoshizumi, K. Hirano, T. Satoh, M.
Miura, Org. Lett. 2009, 11, 3072; f) F. Besselievre, S. Piguel,
Angew. Chem. 2009, 121, 9717; Angew. Chem. Int. Ed. 2009,
48, 9553; g) E. R. Strieter, B. Bhayana, S. L. Buchwald, J. Am.
Chem. Soc. 2009, 131, 78.
[2] D. Leung, W. Du, C. Hardouin, H. Cheng, I. Hwang, B. F.
Cravatt, D. L. Boger, Bioorg. Med. Chem. Lett. 2005, 15, 1423.
[3] a) U. Mitschke, P. Bäuerle, J. Mater. Chem. 2000, 10, 1471; b)
E. V. Zarudnitskii, I. I. Pervak, A. S. Merkulov, A. A. Yur-
cenko, A. A. Tolmachev, Tetrahedron 2008, 64, 10431.
[4] Some recent examples: a) S.-D. Yang, C.-L. Sun, Z. Fang, B.-
J. Li, Y.-Z. Li, Z.-J. Shi, Angew. Chem. 2008, 120, 1495; Angew.
Chem. Int. Ed. 2008, 47, 1473; b) T. Kawano, T. Yoshizumi, K.
Hirano, T. Satoh, M. Miura, Org. Lett. 2009, 11, 3072; c) G.
Cusati, L. Djakovitch, Tetrahedron Lett. 2008, 49, 2499; d) F.
[13] a) J. Mao, J. Guo, J. Fang, S.-J. Ji, Tetrahedron 2008, 64, 3905;
b) J. She, Z. Jiang, Y. Wang, Tetrahedron Lett. 2009, 50, 593.
Received: October 21, 2011
Published Online: December 12, 2011
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