Copper-mediated direct arylation of 1,3,4-oxadiazoles and 1,2,4-triazoles with aryl iodides

Article abstract of DOI:10.1021/ol9011212

The copper-mediated direct arylation of 1,3,4-oxadiazoles and 1,2,4-triazoles with aryl iodides proceeds efficiently in the presence of suitable ligands and bases. This method allows the installation of a variety of aryl moieties bearing a functional group such as ketone, ester, or nitrile so as to enable the facile construction of various functionalized oxadiazole and triazole core π systems.

Full text of DOI:10.1021/ol9011212

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3072-3075
Copper-Mediated Direct Arylation of
1,3,4-Oxadiazoles and 1,2,4-Triazoles
with Aryl Iodides
Tsuyoshi Kawano, Tomoki Yoshizumi, Koji Hirano, Tetsuya Satoh, and
Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity,
Suita, Osaka 565-0871, Japan
miura@chem.eng.osaka-u.ac.jp
Received May 21, 2009
ABSTRACT
The copper-mediated direct arylation of 1,3,4-oxadiazoles and 1,2,4-triazoles with aryl iodides proceeds efficiently in the presence of suitable
ligands and bases. This method allows the installation of a variety of aryl moieties bearing a functional group such as ketone, ester, or nitrile
so as to enable the facile construction of various functionalized oxadiazole and triazole core π systems.
π-Conjugated molecules containing heterocycles constitute
an important class of compounds in material and pharma-
ceutical chemistry. Among them, 2,5-diaryl-1,3,4-oxadiazoles
and 3,4,5-triaryl-1,2,4-triazoles have recently received much
attention in the field of organic electronics because of their
good electron-transporting and hole-blocking abilities.1
Examples of such well-known compounds include 2-(4-
biphenylyl)-5-(4-tert-butylphenyl)-1,3,4-oxadiazole (PBD), 1,3-
[bis(4-tert-butylphenyl)-1,3,4-oxadiazolyl]phenylene (OXD7),
and 3-(4-biphenyl)-4-phenyl-5-tert-butylphenyl-1,2,4-triazole
(TAZ).1a,2 Suitably π-conjugated oxadiazole systems may
also have multiphoton absorbing properties.1b On the other
hand, some oxadiazole derivatives are known to work as ester
and amide bioisosteres.3 Therefore, the development of
effective methods for their concise synthesis and function-
alization is of considerable importance in organic synthesis.
Recently, the metal-mediated direct arylation of heteroare-
nes has been widely studied and is one of the most attractive
approaches to make heteroaryl-aryl linkages.4,5 While the
(4) Recent reviews: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
(c) Campeau, L. C.; Stuart, D. R.; Fagnou, K. Aldrichchim. Acta 2007, 40,
35. (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173.
(5) Recent works: (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 128, 3994. (b) Yanagisawa, S.; Sudo, T.;
Noyori, R.; Itami, K. J. Am. Chem. Soc. 2006, 128, 11748. (c) Stuart, D. R.;
Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072. (d) Stuart,
D. R.; Fagnou, K. Science 2007, 316, 1172. (e) Zhang, Z.; Hu, Z.; Yu, Z.;
Lei, P.; Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48, 2415. (f)
Lewis, J. C.; Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2008, 130, 2493. (g) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc.
2008, 130, 2926. (h) Blaszykowski, C.; Aktoudianakis, E.; Alberico, D.;
Bressy, C.; Hulcoop, D. G.; Jafarpour, F.; Joushaghani, A.; Laleu, B.;
Lautens, M. J. Org. Chem. 2008, 73, 1888. (i) Zhao, J.; Zhang, Y.; Cheng,
K. J. Org. Chem. 2008, 73, 7428. (j) Berman, A. M.; Lewis, J. C.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926. (k) Yang, S.-D.;
Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed.
2008, 47, 1473. (l) Nandurkar, N. S.; Bhanushali, M. J.; Bhor, M. D.;
Bhanage, M. Tetrahedron Lett. 2008, 49, 1045. (m) Cusati, G.; Djakovitch,
L. Tetrahedron Lett. 2008, 49, 2499. (n) Potavathri, S.; Dumas, A. S.;
Dwight, T. A.; Naumiec, G. R.; Hammann, J. M.; DeBoef, B. Tetrahedron
Lett. 2008, 49, 4050. (o) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K.
Tetrahedron 2008, 64, 6073. (p) Ackermann, L.; Althammer, A.; Fenner,
S. Angew. Chem., Int. Ed. 2009, 48, 201. (q) Join, B.; Yamamoto, T.; Itami,
K. Angew. Chem., Int. Ed. 2009, 48, 3644.
(1) (a) Mitschke, U.; Ba¨uerle, P. J. Mater. Chem. 2000, 10, 1471. (b)
He, G. S.; Tan, L.-S.; Zheng, Q.; Prasad, P. N. Chem. ReV. 2008, 108,
1245.
(2) (a) Rehmann, N.; Ulbricht, C.; Ko¨hnen, A.; Zacharias, P.; Gather,
M. C.; Hertel, D.; Holder, E.; Meerholz, K.; Schubert, U. S. AdV. Mater.
2008, 20, 129. (b) Yang, X.; Mu¨ller, D. C.; Nether, D.; Meerholz, K. AdV.
Mater. 2006, 18, 948. (c) Adachi, C.; Baldo, M. A.; Forrest, S. R.;
Thompson, M. E. Appl. Phys. Lett. 2000, 77, 904
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(3) (a) Leung, D.; Du, W.; Hardouin, C.; Cheng, H.; Hwang, I.; Cravatt,
B. F.; Boger, D. L. Bioorg. Med. Chem. Lett. 2005, 15, 1423. (b)
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10.1021/ol9011212 CCC: $40.75
Published on Web 06/24/2009
 2009 American Chemical Society

reactions are often carried out by means of palladium
catalysis, much less expensive copper salts or complexes may
also be used as catalysts or promoters.6-11 In 2007, Daugulis
reported the copper-catalyzed direct arylation of various
heterocycles with aryl iodides using LiO-t-Bu as a base.6
Subsequently, Ackermann7a and Bergmann and Ellman7b
described the direct arylation of 1,2,3-triazoles and benzo-
triazepines, respectively, under similar conditions. Our group
also succeeded in performing the direct arylation of azoles
mediated by copper salts with the aid of carbonate bases.8
Gaunt9 and You10 expanded the scope of the arylating
reagents to the corresponding diaryliodonium(III) salts and
aryl bromides, respectively, and in particular, the reaction
of the hypervalent iodonium salts with benzanilides was
found to induce a unique site selectivity. Given the utilities
of copper salts and complexes in this type of transformation,
we anticipated that the copper-based strategies could be
applied to the reaction with 1,3,4-oxadiazoles and 1,2,4-
trizoles. Herein, we report the copper-mediated direct C5
arylation reactions of 2-aryl-1,3,4-oxadiazoles and 3,4-diaryl-
1,2,4-triazoles.12 The methods allow the use of a variety of
aryl iodides as the arylating reagents and the facile prepara-
tion of various functionalized oxadiazole and triazole core
π systems.
the yield, with phen proving to be optimal (entries 3 and 5).
The choice of base was also crucial for the reaction. Weaker
bases such as Li2CO3 and Na2CO3 were found to dramatically
decrease the yield (entries 6-7). Finally, with use of 20 mol
% of CuI in the presence of 1.0 equiv of Cs2CO3, the reaction
at 100 °C resulted in 83% yield of 3aa after isolation (entry
8). Unexpectedly, LiO-t-Bu completely failed to lead to the
formation of 3aa under the reaction conditions (entry 9).
With the optimized conditions in hand, we carried out the
direct arylation using various oxadiazoles 1 and aryl iodides
2 (Table 2). Not only simple iodobenzene (2a) but also
Table 2. Copper-Catalyzed Direct Arylation of
2-Aryl-1,3,4-oxadiazole (1) with Aryl Iodide (2)a
Based on our previous work,8 we initially examined the
direct arylation of 2-phenyl-1,3,4-oxadiazole (1a) with io-
dobenzene (2a) using CuI (10 mol %), PPh3 (10 mol %),
and K2CO3 (2.0 equiv) in DMSO at 120 °C (Table 1, entry
Table 1. Optimization for Copper-Catalyzed C5 Arylation of
2-Phenyl-1,3,4-oxadiazole (1a) with Iodobenzene (2a)a
entry
ligand
base
3aa, yieldb (%)
c
1
2
3
4
5
6
7
8d
9
PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Na2CO3
Cs2CO3
LiO-t-Bu
37
18
73
33
91
7
31
100(83)
0
TMEDA
DMEDA
bpy
phen
phen
phen
phen
a A mixture of 1 (0.50 mmol), 2 (1.0 mmol), CuI (0.10 mmol), 1,10-
phenanthroline (0.20 mmol), and Cs2CO3 (0.50 mmol) was stirred in DMSO
(1.0 mL) at 100 °C for 4 h. b Isolated yield. c A mixture of 1c (0.50 mmol),
2 (0.60 mmol), CuI (0.050 mmol), 1,10-phenanthroline (0.10 mmol), and
K2CO3 (1.0 mmol) was heated in DMSO (1.0 mL) at 120 °C for 4 h.
phen
a A mixture of 1a (0.50 mmol), 2a (0.60 mmol), CuI (0.050 mmol),
ligand (0.10 mmol), and base (1.0 mmol) was stirred in DMSO (1.0 mL)
for 4 h at 120 °C. b GC yield. Isolated yield is in parentheses. c PPh3 (0.050
mmol). d With CuI (0.10 mmol), phen (0.20 mmol), Cs2CO3 (0.50 mmol),
and 2a (1.0 mmol) at 100 °C.
electron-rich 2b (entry 2) and electron-deficient 2c and 2d
(entries 3 and 4) reacted with 1a effectively. The reaction
with 2e provided the arylated product 3ae in good yield,
leaving the C-Br moiety untouched (entry 5). Taking
advantage of the relatively mild reaction conditions, the
phenyl groups bearing a cyano or carbonyl function were
introduced to the oxadiazole (entries 6 and 7). Methoxy-
1), and the corresponding arylated product 3aa was obtained
albeit with a low yield. We then screened some nitrogen-
based ligands.6,7,11 While the use of N,N,N′,N′-tetramethyl-
ethylenediamine (TMEDA) and 2,2′-bipyridine (bpy) gave
no positive effects (entries 2 and 4), N,N′-dimethylethylene-
diamine (DMEDA) and 1,10-phenanthroline (phen) improved
Org. Lett., Vol. 11, No. 14, 2009
3073

substituted oxadiazole 1b instead of 1a was available for
use. As observed in the reaction with 1a, an array of aryl
iodides took part in the reaction to furnish the corresponding
2,5-diaryl-1,3,4-oxadiazoles 3bb-bf in good to excellent
yields (entries 8-12). On the contrary, the oxadiazole 1c
having a chlorine atom on the benzene ring was found to
decompose rapidly under the standard reaction conditions.
However, the alternative conditions in entry 5 of Table 1
could be applicable to 1c. A number of aryl iodides coupled
with 1c smoothly to afford the expected products in accept-
able yields with the exception of electron-rich 2b (entries
13-17).
By using the modified conditions, we conducted the
reaction of triazole 4 with a number of aryl iodides. As shown
in Scheme 1, electron-withdrawing as well as electron-
Scheme 1
Next, we attempted the direct arylation of 3,4-diphenyl-
4H-1,2,4-triazole (4) as a representative triazole. However,
the reaction with 2a gave no expected coupling product 5a
under the catalytic conditions employed above. Thus, further
optimization studies were performed to achieve the arylation
(Table 3). According to our previous observation,8 we tested
donating groups were compatible under the reaction condi-
tions.
Finally, we undertook the construction of a carbazole-
moiety-containing oxadiazole in a single vessel. Such species
have aroused considerable interest in the field of OLEDs
(Scheme 2).14 Treatment of 2-phenyl-1,3,4-oxadiazole (1a,
Table 3. Optimization for Copper-Promoted C5 Arylation of
3,4-Diphenyl-4H-1,2,4-triazole (4) with Iodobenzene (2a)a
Scheme 2
entry
ligand (equiv)
base
5a, yieldb (%)
1
2
3
4
5
6
7
PPh3 (1.0)
PPh3 (1.0)
PPh3 (1.0)
PPh3 (0.2)
P(o-tolyl)3 (0.2)
PCy3 (0.2)
none
K2CO3
K3PO4
34
50
84(62)
99(75)
64
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
47
58
a A mixture of 4 (0.50 mmol), 2a (0.60 mmol), CuI (0.50 mmol), ligand,
and base (1.0 mmol) was stirred in DMSO (1.0 mL) for 2 h at 160 °C.
b GC yield. Isolated yield is in parentheses.
0.50 mmol) with 2-fluoroiodobenzene (1j, 1.0 mmol) under
copper catalysis followed by the addition of dppe (20 mol
%),15 carbazole (0.75 mmol), and K2CO3 (1.5 mmol)
furnished the bipolar π-conjugated compound 6 in 70%
overall yield through the direct arylation/SNAr reaction
sequence.
Although further efforts on the clarification of the reaction
mechanism are required, one possibility involves the se-
quential base-assisted cupration of azole/σ-bond metathesis
with aryl iodide. In addition, the pathway including trans-
a stoichiometric amount of CuI/PPh3 in the reaction, and the
desired product was obtained in 34% yield with K2CO3 as a
base (entry 1). Subsequent additional investigation into the
effect of base revealed that the use of Na2CO3 or K3PO4
instead of K2CO3 increased the yield (entries 2 and 3). A
decrease in the amount of PPh3 to 0.2 equiv further improved
the reaction efficiency to produce 5a in 75% isolated yield
(entry 4). Other typical phosphines such as P(o-tolyl)3 and
PCy3 showed less efficiency (entries 5 and 6). Even in the
presence of a stoichiometric amount of CuI and a suitable
base, the addition of PPh3 was essential for a satisfactory
yield (entry 7).13
(8) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467. (b) Yoshizumi, T.; Tsurugi, H.; Satoh,
T.; Miura, M. Tetrahedron Lett. 2008, 49, 1598. (c) Yoshizumi, T.; Satoh,
T.; Hirano, K.; Matsuo, D.; Orita, A.; Otera, J.; Miura, M. Tetrahedron
Lett. 2009, 50, 3273.
(6) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
15185.
(9) (a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc.
2008, 130, 8172. (b) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
(10) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J.
Angew. Chem., Int. Ed. 2009, 48, 3296.
(7) (a) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R.
Org. Lett. 2008, 10, 3081. (b) Yotphan, S.; Bergman, R. G.; Ellman, J. A.
Org. Lett. 2009, 11, 1511. See also: (c) Ban, I.; Sudo, T.; Taniguchi, T.;
Itami, K. Org. Lett. 2008, 10, 3607. (d) Besselie`vre, F.; Piguel, S.; Mahuteau-
Betzer, F.; Grierson, D. S. Org. Lett. 2008, 10, 4029.
(11) Ni catalysis for the direct arylation of azoles: (a) Canivet, J.;
Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733. (b) Hachiya,
H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737.
3074
Org. Lett., Vol. 11, No. 14, 2009

metalation of CuI with the metalated azole generated in situ
by the action of base could not be completely retarded.6
In summary, we have described copper-based methods for
the effective direct arylation of 1,3,4-oxadiazole and 1,2,4-
triazole cores with aryl iodides to give rise to the corre-
sponding π-conjugated compounds. The application to the
facile synthesis of the bipolar-type material in a one-pot
manner may also demonstrate its synthetic utility.
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
(12) Daugulis reported one example of the direct arylation with 1-methyl-
1H-1,2,4-triazole: (a) See ref 6b. Palladium-catalyzed direct arylation of
1,2,3-triazoles: (b) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan,
V. Org. Lett. 2007, 9, 2333. (c) Iwasaki, M.; Yorimitsu, H.; Oshima, K.
Chem. Asian J. 2007, 2, 1430. (d) Ackermann, L.; Vicente, R.; Born, R.
AdV. Synth. Catal. 2008, 350, 741.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Although the exact role of PPh3 is not clear at this stage, it may
work as an initiator rather than a ligand. Namely, PPh3 could change the
association state of CuI via its coordination to the Cu center leading to the
monomeric active species.
OL9011212
(14) (a) Guan, M.; Bian, Q.; Zhou, Y. F.; Li, F. Y.; Li, Z. J.; Huang,
C. H. Chem. Commun. 2003, 2708. (b) Tao, Y.; Wang, Q.; Yang, C.; Wang,
Q.; Zhang, Z.; Zou, T.; Qin, J.; Ma, D. Angew. Chem., Int. Ed. 2008, 47,
8104.
(15) Without dppe, the copper-catalyzed amination of unreacted 2j with
carbazole predominantly occurred to decrease the yield of 6. Hence, dppe
seemed to deactivate the copper complex for the amination reaction. Other
phosphines such as PPh3, dppp, and dppb were less effective.
Org. Lett., Vol. 11, No. 14, 2009
3075