ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper(II)-Mediated Dehydrogenative
Cross-Coupling of Heteroarenes
Zhifeng Mao,† Zhe Wang,‡ Zhaoqing Xu,*,†,‡ Fei Huang,† Zhengkun Yu,*,† and
Rui Wang*,‡
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023,
China, and Key Laboratory of Preclinical Study for New Drugs of Gansu Province,
Lanzhou University, Lanzhou 730000, China
xuzq@dicp.ac.cn; zkyu@dicp.ac.cn; wangrui@lzu.edu.cn
Received June 1, 2012
ABSTRACT
Cu(OAc)2-mediated dehydrogenative cross-coupling between two heteroarenes has been realized in the absence of any other additive. A
mechanism involving a formal Cu(II) to Cu(0) route by convergent disproportionation of the copper mediator is proposed and has been evidenced
by copper mirror formation during the reaction. This synthetic protocol provides a concise and “green” access to unsymmetrical biheteroarenes
bearing structural motifs of substantial utility in organic synthesis.
Bi(heteroaryl) structural motifs usually possess interest-
ing biological and physical properties and have been
extensively applied in the preparation of pharmaceuticals
and advanced materials.1 The traditional synthetic route
to biheteroarenes (heteroaromatic biaryls) is transition-
metal-catalyzed cross-coupling of a heteroaryl halide with
another preactivated heteroaryl substrate.2 During the
past decades, much effort was made toward the direct
arylation/heteroarylation of heteroaromatic CÀH bonds.3,4
In this context, direct CÀH/CÀH cross-coupling between
two heteroarenes represents the most concise route to
biheteroarenes.5,6 A palladium catalyst combined with a
stoichiometric amount of metal oxidants such as Cu(II),
Cu(II)/Ag(I), or Cu(II)/Cu(I) reagents was usually re-
quired (Scheme 1, path A).7 A stepwise procedure was
developed by Daugulis et al. for the synthesis of unsym-
metrical biheteroarenes via a base-mediated deprotonation/
iodination and Cu(I)-catalyzed CÀH arylation sequence
(path B).8 From the viewpoint of economical and envi-
ronmental consideration, it is highly desirable to employ
less expensive metal catalysts/mediators and avoid the
† Dalian Institute of Chemical Physics.
‡ Lanzhou University.
(1) Hughes, R. A.; Moody, C. J. Angew. Chem., Int. Ed. 2007, 46,
7930.
(2) Ackermann, L. Modern Arylation Methods; Wiley-VCH: Wein-
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(3) For selected recent reviews, see: (a) Chen, X.; Engle, K. M.;
Wang, D.-H; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Daugulis, O.; Do,
H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (d) Ashenhurst,
J. A. Chem. Soc. Rev. 2010, 39, 540. (e) Campeau, L.-C; Fagnou, K.
Chem. Commun. 2006, 1253.
(4) For selected recent examples, see: (a) Ackermann, L.; Althammer,
A.; Fenner, S. Angew. Chem., Int. Ed. 2009, 48, 201. (b) Zhao, D.; Wang,
W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J. Angew. Chem., Int. Ed.
2009, 48, 3296. (c) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2009, 11, 1737. (d) Huang, J.; Chan, J.; Chan, Y.; Borths, C. J.;
Baucom, K. D.; Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132,
3674. (e) Tredwell, M. J.; Gulias, M.; Gaunt, B. N.; Johansson, C. C. C.;
Collins, B. S. L.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 1076. (f)
Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed.
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T.; Miura, M. ChemCatChem. 2010, 2, 1403.
(5) Zhao, D.; You, J.; Hu, C. Chem.;Eur. J. 2011, 17, 5466.
(6) For Pd-catalyzed decarboxylative CÀH heteroarylation of
azoles, see: Zhang, F.; Greaney, M. F. Angew. Chem., Int. Ed. 2010,
49, 2768.
(7) (a) Bugaut, X.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 7479.
(b) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J. J.
Am. Chem. Soc. 2010, 132, 1822. (c) Wang, Z.; Li, K.; Zhao, D.; Lan, J.;
You, J. Angew. Chem., Int. Ed. 2011, 50, 5365. (d) Gong, X.; Song, G.;
Zhang, H.; Li, X. Org. Lett. 2011, 13, 1766. (e) Yamaguchi, A. D.;
Mandal, D.; Yamaguchi, K.; Itami, K. Chem. Lett. 2011, 40, 555. (f)
Han, W.; Mayer, P.; Ofial, A. R. Angew. Chem., Int. Ed. 2011, 50, 2178.
(g) Dong, J.; Huang, Y.; Qin, X.; Cheng, Y.; Hao, J.; Wan, D.; Li, W.;
Liu, X.; You, J. Chem.;Eur. J. 2012, 18, 6158.
(8) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2011, 133, 13577.
r
10.1021/ol301517y
XXXX American Chemical Society