Copper-mediated annulative direct coupling of o -alkynylphenols with oxadiazoles: A dehydrogenative cascade construction of biheteroaryls

Article abstract of DOI:10.1021/ol200975j

A copper-mediated annulative direct coupling of o-alkynylphenols with 1,3,4-oxadiazoles proceeds smoothly even under ambient conditions to afford the corresponding biheteroaryls. The reaction system represents a new avenue for the construction of bihetero

Full text of DOI:10.1021/ol200975j

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3076–3079
Copper-Mediated Annulative Direct
Coupling of o-Alkynylphenols with
Oxadiazoles: A Dehydrogenative Cascade
Construction of Biheteroaryls
Hitoshi Hachiya, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Received April 13, 2011
ABSTRACT
A copper-mediated annulative direct coupling of o-alkynylphenols with 1,3,4-oxadiazoles proceeds smoothly even under ambient conditions to
afford the corresponding biheteroaryls. The reaction system represents a new avenue for the construction of biheteroaryl molecules of interest in
their biological and physical properties.
Various biaryls containing heterocyclic cores constitute
an important class of compounds in chemical synthesis
owing to their ubiquity in pharmaceuticals, biologically
active compounds, and functional materials.1 In addition
to the conventional cross-coupling methodology using
organic halides and organometallic reagents, the metal-
mediated CÀH functionalization has recently received
great interest for the synthesis of this type of molecule.2
In particular, an oxidative, dehydrogenative biaryl cou-
pling is quite attractive because it can avoid the use of
halogenated and metalated starting materials. To date,
many successful examples based on a combination of
palladium catalysts and a stoichiometric amount of ex-
ternalmetal oxidantssuchascopper and silver species have
been reported.3,4 While valuable, these precedents still rely
on the precious palladium catalysts. From an economical
point of view, further developments of less expensive
reaction systems are strongly desired. In this context, we
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Iwata, M.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 1301. (b) Kita, Y.;
Morimoto, K.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. Chem. Soc. 2009,
131, 1668.
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Chem. Rev. 2002, 102, 1359. (b) Corbet, J.-P.; Mignani, G. Chem. Rev.
2006, 106, 2651.
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Rev. 2007, 107, 174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
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Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (i) Kulkarni,
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r
10.1021/ol200975j
Published on Web 05/17/2011
2011 American Chemical Society

previously succeeded in the palladium-free, copper-
mediated intermolecular direct biaryl coupling of azoles
with 2-arylazines (Scheme 1 a).5 The reaction is believed to
proceed through (i) direct CÀH cupration of azoles,6 (ii)
chelation-assisted second CÀH cupration of arylazines,7
and (iii) productive reductive elimination. In the course of
our studies on this chemistry, we envisaged that the second
CÀH cupration step could be replaced with the annulative
cupration of o-alkynylphenols (Scheme 1 b).8 Thus, if the
cascade process were feasible, an indirect but formally
dehydrogenative biheteroaryl coupling would be realized,
leading to a new type of oxidative biaryl construction from
nonhalogenated and nonmetalated starting materials.
Scheme 1. Oxidative, Dehydrogenative Biaryl Couplings
Mediated by Copper (Py = 2-Pyridyl)
(5) Kitahara, M.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M.
J. Am. Chem. Soc. 2011, 133, 2160.
(6) For selected recent examples, see: (a) Do, H.-Q.; Daugulis, O.
J. Am. Chem. Soc. 2007, 129, 12404. (b) Yoshizumi, T.; Tsurugi, H.;
Satoh, T.; Miura, M. Tetrahedron Lett. 2008, 49, 1598. (c) Yotphan, S.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2009, 11, 1511. (d) Monguchi,
D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607.
(e) Yoshizumi, T.; Satoh, T.; Hirano, K.; Matsuo, D.; Orita, A.; Otera,
J.; Miura, M. Tetrahedron Lett. 2009, 50, 3273. (f) Kawano, T.; Yoshi-
zumi, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 3072.
(g) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org.
Lett. 2008, 10, 3081. (h) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.;
Moreover, the expected structures, 1,3,4-oxadiazole-con-
taining biaryls, exhibited a broad spectrum of physical9
and biological10 activities so that the reaction appears to be
of importance in synthetic chemistry.
Based on the above assumption, we began our optimiza-
tion studies with 2-(phenylethynyl)phenol (1a) and 2-phe-
nyl-1,3,4-oxadiazole (2a) as model substrates. In an initial
experiment, treatment of 1a with 2a in the presence of
CuF2, 1,10-phenanthroline (phen), and K3PO4 in N,
ꢀ
Gao, G.; You, J. Angew. Chem., Int. Ed. 2009, 48, 3296. (i) Besselievre, F.;
Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553. (j) Kitahara, M.; Hirano,
K.; Tsurugi, H.; Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 1772.
(k)Kawano, T.; Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2010, 75, 1764. (l) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M.
J. Am. Chem. Soc. 2010, 132, 6900.
(7) For copper-mediated direct functionalization of arylazines, see:
(a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790. (b) Uemura, T.; Imoto, S.; Chatani, N. Chem. Lett.
2006, 35, 842. (c) Mizuhara, T.; Inuki, S.; Oishi, S.; Fujii, M.; Ohno, H.
Chem. Commun. 2009, 3413. (d) Shuai, Q.; Deng, G.; Chua, Z.; Bohle,
D. S.; Li, C.-J. Adv. Synth. Catal. 2010, 352, 632. (e) Chu, L.; Yue, X.;
Qing, F.-L. Org. Lett. 2010, 12, 1644. (f) Wang, W.; Luo, F.; Zhang, S.;
Cheng, J. J. Org. Chem. 2010, 75, 2415.
Table 1. Optimization Studies for Copper-Mediated Dehydro-
genative Annulative Coupling of 2-(Phenylethynyl)phenol (1a)
with 2-Phenyl-1,3,4-oxadiazole (2a)a
(8) For reviews of metal-mediated annulation of o-alkynylphenols
and -anilines, see: (a) Patil, N. T.; Yamamoto, Y Chem. Rev. 2008, 108,
3395. (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem.
2011, 9, 641. Selected examples:(c) Hiroya, K.; Itoh, S.; Sakamoto, T. J.
Org. Chem. 2004, 69, 1126. (d) Arcadi, A.; Cacchi, S.; Rosario, M. D.;
Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280. (e) Hu, Y.;
Nawoschilk, K. J.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z. J. Org. Chem.
2004, 69, 2235. (f) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E.
Angew. Chem., Int. Ed. 2006, 45, 944. (g) Nakamura, M.; Ilies, L.;
Otsubo, S.; Nakamura, E. Org. Lett. 2006, 8, 2803. (h) Trost, B. M.;
McClory, A. Angew. Chem., Int. Ed. 2007, 46, 2074. (i) Tsuji, H.; Mitsui,
C.; Ilies, L.; Sato, Y.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 11902.
entry
Cu/ligand (ratio)
base
solvent 3aa, % yieldb
1
2
CuF2/phen (10:1)
CuF2/phen (10:1)
CuF2/phen (10:1)
CuBr2/phen (10:1)
K3PO4
DMAc
36
ꢀ
(j) Martınez, C.; Alverez, R.; Aurrecoechea, J. M. Org. Lett. 2009, 11,
Cs2CO3 DMAc
Na2CO3 DMAc
27
1083. (k) Isono, N.; Lautens, M. Org. Lett. 2009, 11, 1329. (l) Swamy,
ꢀ
3
trace
N. K.; Yazici, A.; Pyne, S. G. J. Org. Chem. 2010, 75, 3412. (m) Alverez,
R.; Martınez, C.; Madich, Y.; Denis, J. G.; Aurrecoechea, J. M.; de Lera,
4
K3PO4
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
xylene
DMF
5
ꢀ
c
A. R. Chem.;Eur. J. 2010, 16, 12746. (n) Hirano, K.; Satoh, T.; Miura,
5
Cu(OAc)2/phen (10:1) K3PO4
Cu(acac)2/phen (10:1) K3PO4
Cu(OTf)2/phen (10:1) K3PO4
trace
M. Org. Lett. 2011, 13, 2395. (o) Ye, Y.; Fan, R. Chem. Commun. 2011,
47, 5626.
c
6
19
7
0
€
(9) (a) Mitschke, U.; Bauerle, P. J. Mater. Chem. 2000, 10, 1471. (b)
Adachi, C.; Baldo, M. A.; Forrest, S. R.; Thompson, M. E. Appl. Phys.
8
CuF2/bpy (10:1)
CuF2/TMEDA (10:1)
CuF2/phen (10:1)
CuF2/phen (10:1)
CuF2/phen (10:1)
CuF2/phen (2:1)
CuF2/phen (1:1)
CuF2/none
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
0
Lett. 2000, 77, 904. (c) Guan, M.; Bian, Q.; Zhou, Y. F.; Li, F. Y.; Li,
9
4
€
Z. J.; Huang, C. H. Chem. Commun. 2003, 2708. (d) Yang, X.; Muller,
10
11
12
13
14
15
0
D. C.; Nether, D.; Meerholz, K. Adv. Mater. 2006, 18, 948. (e) Rehmann,
47
€
N.; Ulbricht, C.; Kohnen, A.; Zacharias, P.; Gather, M. C.; Hertel, D.;
DMSO
DMF
41
Holder, E.; Meerholz, K.; Schubert, U. S. Adv. Mater. 2008, 20, 129.
(f) He, G. S.; Tan, L.-S.; Zheng, Q.; Prasad, P. N. Chem. Rev. 2008, 108,
1245. (g) Tao, Y.; Wang, Q.; Yang, C.; Wang, Q.; Zhang, Z.; Zou, T.;
Qin, J.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 8104. (h) Shchekotikhin,
A. E.; Shevtsova, E. K.; Traven, V. F. Russ. J. Org. Chem. 2007, 43, 1686.
(10) (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) Zarudnitskii, E. V.; Pervak, I. I.; Merkulov, A. S.; Yurchenko, A. A.;
Tolmachev, A. A. Tetrahedron 2008, 64, 10431. (c) Peters, D.; Olsen,
G. M.; Nielsen, E. O.; Jorgensen, T. D.; Ahring, P. K. PCT Int. Appl.
2004, WO 2004029053, A1 20040408.
93 (75)
73
DMF
c
DMF
0
a Reaction conditions: Cu (0.60 mmol), ligand, base (0.90 mmol), 1a
(0.30 mmol), 2a (0.60 mmol), solvent (1.0 or 2.0 mL), rt, 8À45 h, air.
b The yields are determined by GC method. Yield of isolated product is
in parentheses. c With 0.60 mmol of K3PO4.
Org. Lett., Vol. 13, No. 12, 2011
3077

N-dimethylacetamide (DMAc) provided the desired bihe-
teroaryl 3aa in 36% GC yield (Table 1, entry 1), while with
moderate efficiency the reaction proceeded even under
ambient conditions (under air at room temperature).11
With the preliminary result in hand, we investigated
various reaction parameters. Replacement of K3PO4 with
Cs2CO3 and Na2CO3 (entries 2 and 3) or other copper salts
such as CuBr2, Cu(OAc)2, Cu(acac)2, and Cu(OTf)2
(entries 4À7) decreased the reaction efficiency. The change
of ligand into bpy and TMEDA also failed to improve the
yield (entries 8 and 9). On the other hand, solvent screening
revealed that polar, aprotic solvents are essential, with N,
N-dimethylformamide (DMF) proving to be optimal
(entries 10À12). Additional optimization indicated that
the ratio of Cu/ligand was a crucial factor: ahalfequivalent
of phen (to CuF2) dramatically increased the yield to 93%
GC yield (75% yield after isolation, entry 13). A higher
loading gave no longer positive effect on the yield (entry
14), while the absence of phen resulted in no formation of
3aa (entry 15).
demanding naphthyl ring did not interfere with the reac-
tion (3af). Moreover, the alkyl-substituted oxadiazole also
could be converted to the biheteroaryl 3ag with the synthe-
tically useful yield.
Scheme 3. Products of the Copper-Mediated Annulative Direct
Coupling of Various o-Alkynylphenols 1 with 2-Phenyl-1,3,
4-oxadiazole (2a)
Scheme 2. Copper-Mediated Annulative Direct Coupling of
2-(Phenylethynyl)phenol (1a) with Various 2-Substituted-1,3,
4-oxadiazoles 2
The functional compatibility on the phenols 2 was
also investigated. The results are summarized in Scheme
3. While the introduction of electron-rich substituents
had no influence on the reaction outcome (3baÀca), the
chloro and trifluoromethyl groups resulted in some-
what lower efficiency (3daÀea). In addition to the
benzene derivatives, a heteroaryl function, thiophene
ring, was also tolerated (3fa). The conjugated enyne
produced the corresponding 3ga with the olefinic moiety
left intact. Notably, the copper-based process accom-
modated bulky alkyl substitutions at alkyne terminus
(3haÀia).
Subsequently, we examined the scope of 1,3,4-oxadia-
zoles 2 in the annulative coupling (Scheme 2). The sub-
strates bearing electron-donating as well as electron-
withdrawing groups showed similar reactivity to create
the corresponding benzofuran-oxadiazole linkages in
moderate to good yields (3abÀae). The sterically
Owing to the inexpensiveness and relatively low toxicity
of copper salt, the above reaction system appears to be
useful from economical and synthetic points of view
despite the inevitable excess amount of copper for the full
(12) MnO2 for an oxidation of Cu(I) into Cu(II): (a) Zhang, W.;
Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948. (b) Sequeira, F. C.;
Turnpenny, B. W.; Chemler, S. R. Angew. Chem., Int. Ed. 2010, 49,
6365.
(11) The reaction under N2 and O2 dropped the yield to 8% and 21%
yields, respectively.
3078
Org. Lett., Vol. 13, No. 12, 2011

identical conditions, the biheteroaryls 3aa and 3af were
obtained with somewhat lower yields (Scheme 4).
Although further improvements are essential, the catalysis
shows the high potential of a Cu(II) catalyst for the
oxidative, dehydrogenative biaryl coupling.13
Scheme 4
In conclusion, we have developed a room-temperature,
copper-mediated annulative direct coupling of o-alkynyl-
phenols with oxadiazoles as a new, unique method for the
construction of biheteroaryls. Moreover, the possibility of
catalysis using CuF2/MnO2 is also described. Detailed
mechanistic studies and application to other arene
systems14 are now in progress.
conversion. Nevertheless, the catalytic version is much
more appealing. Our extensive screening of co-oxidants
for CuF2 revealed that MnO2 could render the reaction
catalytic on copper (Scheme 3).12 With 20 mol % of CuF2,
2.0 equiv of MnO2, and 2.0 equiv of phen, under otherwise
Acknowledgment. This work was partly supported by
Grants-in-Aid from MEXT and JSPS, Japan. K.H. ac-
knowledges Kansai Research Foundation for the Promo-
tion of Science.
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) Without CuF2, the product was not obtained at all. Under
5 mol % catalyst loading, 3aa was formed in 10% yield (GC).
(14) Under the present conditions, attempts to apply aniline analo-
gues, benzoxazole, or benzothiazole were unsuccessful. Further optimi-
zation and details will be reported in due course.
Org. Lett., Vol. 13, No. 12, 2011
3079