attract interest. First, considerable attention has been focused
on the development of cheap, experimentally simple, ligand-
free catalytic systems.5 Second, the use of aryl iodides to obtain
the mild reaction conditions or to replace the expensive transition
metal catalyst, usually palladium or rhodium, with a cheaper
one would also be highly desirable.5e,f,6,7 Herein we wish to
disclose a surprising discovery that the copper-catalyzed N-
arylation of nitrogen-containing heterocycles with aryl iodides
is easily performed in the absence of additional ligand under
very mild conditions.
Considering N-arylimidazoles have been recurrent templates
in medicinal chemistry, a preliminary survey of reaction
conditions was conducted with iodobenzene (1a) and imidazole
(2a) as model arylating agents. Among the solvents tested, DMF
was clearly the best choice (entries 1-4, Table 1). After
screening a variety of bases (i. e., K2CO3, K3PO4, and Cs2CO3),
we found that K3PO4 gave the best result of 93% yield in DMF
(entries 4-6, Table 1). Among these copper sources, CuI is
the most effective (entries 4, 7, and 8, Table 1). Subsequently,
we studied the effect of the amount of CuI on the reaction
efficiency, and found that the negative effect was observed while
the amount of CuI was reduced (entries 4 and 9-11, Table 1).
In addition, we further investigated the cross-coupling reaction
by adding some nitrogen-containing ligands. However, we
surprisingly found that the effect of ligand is almost ignored as
compared to the reactions without additional ligand. For
example, using 20 mol % of L-proline as ligand afforded the
desired product in 92% yield (entry 13, Table 1).
Highly Functional Group Tolerance in
Copper-Catalyzed N-Arylation of
Nitrogen-Containing Heterocycles under Mild
Conditions
Liangbo Zhu, Gaocan Li, Liang Luo, Peng Guo, Jingbo Lan,
and Jingsong You*
Key Laboratory of Green Chemistry and Technology of
Ministry of Education, College of Chemistry, and State Key
Laboratory of Biotherapy, West China Hospital, West China
Medical School, Sichuan UniVersity, 29 Wangjiang Road,
Chengdu 610064, People’s Republic of China
ReceiVed December 4, 2008
A copper-catalyzed process has been developed for the
N-arylation reaction under very mild conditions in the
absence of additional ligand. This protocol could not only
tolerate an array of thermally sensitive functional groups,
but also achieve high chemoselectivity.
With optimized conditions now in hand, we explored the
scope of this process with respect to aryl iodide structure. To
our delight, the N-arylation of imidazole was smoothly per-
formed with the extensive pool of aryl iodides to afford the
corresponding products in good to excellent yields although the
amount of catalyst used is slightly high and the reaction time is
relatively longer if compared to other protocols reported in the
Transition-metal-catalyzed Ullmann-type coupling is one of
the most important methods for the formation of C(aryl)-N,
C(aryl)-C, C(aryl)-O, and C(aryl)-S bonds.1 However, the
classic Ullmann reactions are generally conducted under harsh
reaction conditions such as elevated temperatures as high as
200 °C, use of stoichiometric amounts of copper reagents, and
moderate yields.1,2 In the past few years, much attention has
been paid to improvement of these types of transformations,
and a number of ligands have thereby been developed to
expedite the reaction rates and substantially lower the reaction
temperatures (mostly to the range of 110-130 °C).3,4 In spite
of significant progress, most of these methodologies remain
restricted to a certain degree owing to unavailability, high
expense, air or moisture sensitivity, and/or specificity of
ligands.1-4 Consequently, taking into consideration an industrial
and practical standpoint, some new strategies are starting to
(4) Foe selected copper-catalyzed reactions, see: (a) Antilla, J. C.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (b) Antilla, J. C.;
Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578. (c)
Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Chem. Eur. J. 2004,
10, 5607. (d) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Eur. J.
Org. Chem. 2004, 695. (e) Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler,
J. F.; Taillefer, M. Org. Lett. 2004, 6, 913. (f) Zhang, H.; Cai, Q.; Ma, D. J.
Org. Chem. 2005, 70, 5164. (g) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y.
Chem. Eur. J. 2006, 12, 3636. (h) Guo, X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y.
AdV. Synth. Catal. 2006, 348, 2197. (i) Ma, H.; Jiang, X. J. Org. Chem. 2007,
72, 8943. (j) Xia, N.; Taillefer, M. Chem. Eur. J. 2008, 14, 6037.
(5) Selected examples in the absence of additional ligand: (a) Choudary,
B. M.; Sridhar, C.; Kantam, M. L.; Venkanna, G. T.; Sreedhar, B. J. Am. Chem.
Soc. 2005, 127, 9948. (b) Correa, A.; Bolm, C. AdV. Synth. Catal. 2007, 349,
2673. (c) Taillefer, M.; Xia, N.; Oualli, A. Angew. Chem., Int. Ed. 2007, 46,
934. (d) Zhao, Y.; Wang, Y.; Sun, H.; Li, L.; Zhang, H. Chem. Commun. 2007,
3186. (e) Rout, L.; Sen, T. K.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2007,
46, 5583. (f) Sperotto, E.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G.
J. Org. Chem. 2008, 73, 5625. (g) Zhu, R.; Xing, L.; Wang, X.; Cheng, C.; Su,
D.; Hu, Y. AdV. Synth. Catal. 2008, 350, 1253. (h) Kelkar, A. A.; Patil, N. M.;
Chaudhari, R. V. Tetrahedron Lett. 2002, 43, 7143.
(6) The coupling of aryl iodides: (a) Kwong, F. Y.; Buchwald, S. L. Org.
Lett. 2002, 4, 3517. (b) Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46,
8862. (c) Bistri, O.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 586.
(d) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 2880. (e)
Carril, M.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 4862.
(7) Selected copper-catalyzed reactions under mild conditions: (a) Shafir, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742. (b) Shafir, A.; Lichtor,
P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490. (c) Lv, X.; Bao, W.
J. Org. Chem. 2007, 72, 3863.
(1) For reviews of transition-metal-catalyzed reactions, see: (a) Muci, A. R.;
Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (b) Ley, S. V.; Thomas,
A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c) Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F.,; de MeijereA. Eds.; , Wiley-VCH: Weinheim,
Germany, 2004. (d) Hartwig, J. F. Synlett 2006, 1283. (e) Corbet, J.-P.; Mignani,
G. Chem. ReV. 2006, 106, 2651.
(2) For reviews of copper-catalyzed reactions, see: (a) Kunz, K.; Scholz, U.;
Ganzer, D. Synlett 2003, 2428. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. ReV. 2004, 248, 2337.
(3) Two breakthroughs from the research groups of Taillefer and Buchwald: (a)
Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 7727. (b) Taillefer, M.; Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F. Fr
2833947-WO 0353225 (Pr. Nb. Fr 2001 16547), 2001.
2200 J. Org. Chem. 2009, 74, 2200–2202
10.1021/jo802669b CCC: $40.75 2009 American Chemical Society
Published on Web 02/05/2009