Pyridine N-oxides as ligands in Cu-catalyzed Af-arylation of imidazoles in water

Article abstract of DOI:10.1021/ol9010773

N-Arylation of imidazoles with aryl halides catalyzed by a combination of copper(II) sulfate and 1,2-bis(2-pyridyl)-ethane-N,N′-dioxide in water afforded up to 95% yield.

Full text of DOI:10.1021/ol9010773

ORGANIC
LETTERS
2
009
Vol. 11, No. 15
294-3297
Pyridine N-Oxides as Ligands in
Cu-Catalyzed N-Arylation of Imidazoles
in Water
3
†
Lei Liang, Zhengkai Li, and Xiangge Zhou*
†
,†,‡
Institute of Homogeneous Catalysis, College of Chemistry, Sichuan UniVersity,
Chengdu 610064, China, and State Key Laboratory of Coordination Chemistry,
Nanjing UniVersity, Nanjing 210093, China
zhouxiangge@scu.edu.cn
Received May 18, 2009
ABSTRACT
N-Arylation of imidazoles with aryl halides catalyzed by a combination of copper(II) sulfate and 1,2-bis(2-pyridyl)-ethane-N,N′-dioxide in water
afforded up to 95% yield.
5
N-Arylimidazoles play an important role in a wide range of
classical Ullmann-type coupling reactions. In both cases,
the reactions suffered from several drawbacks such as harsh
reaction conditions (Ullmann reaction requires high temper-
ature, extended reaction time), stoichiometric amounts of
copper reagents, and low tolerance of functional groups,
which limited their applications. A breakthrough has been
made by Buchwald and co-workers who discovered that the
Cu-catalyzed N-arylation of nitrogen-containing heterocycles
with aryl halides could be achieved in good yields under
pharmaceuticals, natural products, and biologically active
1
compounds and have been exploited as precursors of
2
versatile N-heterocyclic carbenes, efficient ligands for
3
4
transition-metal catalysis or ionic liquids. Traditionally,
these moieties are prepared by nucleophilic aromatic sub-
stitution of imidazoles by activated aryl halides or the
†
Sichuan University.
Nanjing University.
‡
6
mild conditions in the presence of bidentate N,N-ligands.
Following these pioneering works, a number of Cu-catalyzed
(
1) For recent reviews, see: (a) Wiglenda, T.; Ott, I.; Kircher, B.;
Schumacher, P.; Schuster, D.; Langer, T.; Gust, R. J. Med. Chem. 2005,
8, 2126. (b) Jin, Z. Nat. Prod. Rep. 2005, 22, 196. (c) De Luca, L. Curr.
Med. Chem. 2006, 13, 1. (d) Campeau, L.-C.; Fagnou, K. Chem. Soc. ReV.
007, 36, 1173. (e) Wiglenda, T.; Gust, R. J. Med. Chem. 2007, 50, 1475.
f) Kison, C.; Opatz, T. Chem.sEur. J. 2009, 15, 843.
2) (a) Vargas, V. C.; Rubio, R. J.; Hollis, T. K.; Salcido, M. E. Org.
4
2
(5) For reviews of copper-catalyzed cross-coupling reactions, see: (a)
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (b)
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (c) Kunz, K.; Scholz,
U.; Ganzer, D. Synlett 2003, 2428. (d) Beletskaya, I. P.; Cheprakov, A. V.
Coord. Chem. ReV. 2004, 248, 2337. (e) Evano, G.; Blanchard, N.; Toumi,
M. Chem. ReV. 2008, 108, 3054.
(
(
Lett. 2003, 5, 4847. (b) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.;
Reibenspies, J. H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113. (c)
Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606.
(
3) (a) Beller, M.; Harkal, S.; Rataboul, F.; Zapf, A.; Fuhrmann, C.;
Riermeier, T.; Monsees, A. AdV. Synth. Catal. 2004, 346, 1742. (b) Rataboul,
F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.;
Dingerdissen, U.; Beller, M. Chem.sEur. J. 2004, 10, 2983. (c) Schulz,
T.; Torborg, C.; Sch a¨ ffner, B.; Huang, J.; Zapf, A.; Kadyrov, R.; B o¨ rner,
A.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 918.
(6) See the important references: (a) Klapars, A.; Antilla, J. C.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (b) Antilla, J. C.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (c)
Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem.
2004, 69, 5578. (d) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8,
2779. (e) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem.
2007, 72, 6190. (f) Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am.
Chem. Soc. 2009, 131, 78.
(4) (a) Baltus, R. E.; Culbertson, B. H.; Dai, S.; Luo, H.; DePaoli, D. W.
J. Phys. Chem. B 2004, 108, 721. (b) Su a´ rez-Pantiga, S.; Rubio, E.; Alvarez-
R u´ a, C.; Gonz a´ lez, J. Org. Lett. 2009, 11, 13.
10.1021/ol9010773 CCC: $40.75
Published on Web 07/02/2009
 2009 American Chemical Society

7
coupling reactions with various ligands have been reported.
aspect, the development of less expensive and more sustain-
able catalysts in water remains an elusive goal in modern
synthetic chemistry.
In continuation of our endeavors to develop environmen-
tally friendly protocols, herein we disclose N-arylation of
imidazoles with aryl halides catalyzed by readily available
Nevertheless, room for exploration of an efficient ligand-
assisted catalytic system, especially in the aqueous phase,
8
still remains.
On the other hand, amine as well as its N-oxide derivatives
have long been recognized as ligands in coordination
chemistry (Figure 1), and pyridine N-oxides, well-known
9
4
CuSO with pyridine N-oxide ligands in water.
Iodobenzene and imidazole were initially chosen as models
for the coupling reaction in water. The standardized protocol
was carried out by using imidazole (1.1 equiv), iodobenzene
(
(
1 equiv), base (2 equiv), Cu source (10 mol %), and ligand
20 mol %) in water at 120 °C for 24 h. The results are
shown in Table 1.
Table 1. Screening Reaction Conditions for N-Arylation of
a
Imidazole with Iodobenzene
Figure 1. Amine and N-oxide ligands employed in this work.
b
entry
Cu source
ligand
base
yield (%)
1
2
3
4
5
6
7
8
9
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
4
4
4
4
4
4
4
4
4
4
·5H
·5H
·5H
·5H
·5H
·5H
·5H
·5H
·5H
·5H
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
L1
L2
L3
L3
L4
L5
L6
L3
L3
L3
L3
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
26
78
91
69
8
5
for their superior solubilities in water, can be viewed as
neutral structural analogues of the widely popular anionic
phenolate systems. However, application of N-oxides in
metal-mediated cross-coupling reactions has not yet been
reported.
1
0
c
In general, many achievements of synthesis in organic
solvents inherently have the problem of pollution. Consider-
ing the requirement of green chemistry, the development of
6
K
K
2
CO
PO
3
12
34
66
0
3
4
11
10
KOH
a more environmentally benign reaction would be desirable.
11
12
13
14
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
Thus, synthesis of organic molecules in water is an exten-
sively investigated topic which entails the additional chal-
CuSO
CuI
4
·5H
2
O
9
L3
L3
L3
L3
L3
L3
L3
73
77
16
12
36
12
lenges of water tolerance for the catalyst and the associated
problem of substrate solubilities and reactivities. In this
CuCl
Cu(OAc)2
Cu
CuClO
2
15
2
Cs CO
1
1
6
7
2
O
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
(
7) (a) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M.
4
d
Chem.sEur. J. 2004, 10, 5607. (b) Monnier, F.; Taillefer, M. Angew. Chem.,
Int. Ed. 2008, 47, 3096. (c) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem.
18
CuSO
CuSO
4
·5H
2
O
O
87
e
19
4
·5H
2
50
2005, 70, 5164. (d) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett.
2002, 4, 581. (e) Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald,
a
Unless otherwise noted, the reactions were carried out with imidazole
CO (2.00 mmol), CuSO (10
(
1.10 mmol), iodobenzene (1.00 mmol), Cs
mol %), and L3 (20 mol %) in water (3 mL) at 120 °C for 24 h.
Determined by GC/MS. The reaction was performed with CuSO
) and L3 (10 mol %) in water (3 mL) at 120 °C for 36 h. (n-Bu)
32.2 mg, 0.1 mmol) was added as PTC. The reaction temperature was
00 °C.
2
3
4
S. L. J. Org. Chem. 2003, 68, 4367. (f) Kwong, F. Y.; Buchwald, S. L.
Org. Lett. 2003, 5, 793. (g) Jerphagnon, T.; van Klink, G. P. M.; de Vries,
J. G.; van Koten, G. Org. Lett. 2005, 7, 5241. (h) Xie, Y.-X.; Pi, S.-F.;
Wang, J.; Yin, D.-L.; Li, J.-H. J. Org. Chem. 2006, 71, 8324. (i) Liu, L.;
Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P. J. J. Org. Chem.
b
c
4
(5 mol
NBr
d
%
(
1
4
e
2
005, 70, 10135. (j) Zhu, L.; Cheng, L.; Zhang, Y.; Xie, R.; You, J. J.
Org. Chem. 2007, 72, 2737. (k) Lv, X.; Bao, W. J. Org. Chem. 2007, 72,
3
863. (l) Guo, X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. AdV. Synth. Catal.
007, 348, 2197. (m) Ma, H.; Jiang, X. J. Org. Chem. 2007, 72, 8943. (n)
2
Cheng, D.; Gan, F.; Qian, W.; Bao, W. Green Chem. 2008, 10, 171.
Among the ligands used, pyridine N-oxides were more
(
8) For reviews of Cu-catalyzed cross-coupling reactions with the
beneficial to the catalysis than their pyridine analogues, and
L3 exhibited much higher catalytic ability than the other two
N-oxide ligands (Table 1, entries 1-7). The excellent
solubility in water and the flexibility of ligand structure
probably contributed the high efficiency of L3. Different
copper sources have also been examined, and the catalysis
by CuSO
product in good yields of 91%, 73%, and 77%, respectively
Table 1, entries 3, 13, and 14). However, the employment
participation of water or in water, see: (a) Rao, H.; Fu, H.; Jiang, Y.; Zhao,
Y. J. Org. Chem. 2005, 70, 8107. (b) Lu, Z.; Twieg, R. J.; Huang, S. D.
Tetrahedron Lett. 2003, 44, 6289. (c) Lu, Z.; Twieg, R. J. Tetrahedron
Lett. 2005, 46, 2997. (d) Zhu, X.; Ma, Y.; Su, L.; Song, H.; Chen, G.;
Liang, D.; Wan, Y. Synthesis 2006, 3955. (e) Yadav, L. D. S.; Yadav, B. S.;
Rai, V. K. Synthesis 2006, 1868. (f) R o¨ ttger, S.; Sj o¨ berg, P. J. R.; Larhed,
M. J. Comb. Chem. 2007, 9, 204. (g) Carril, M.; SanMartin, R.; Dom ´ı nguez,
E.; Tellitu, I. Green Chem. 2007, 9, 219. (h) Carril, M.; SanMartin, R.;
Tellitu, I.; Dom ´ı nguez, E. Org. Lett. 2006, 8, 1467. (i) Barbero, N.; Carril,
M.; SanMartin, R.; Dom ´ı nguez, E. Tetrahedron 2007, 63, 10425. (j) Carril,
M.; SanMartin, R.; Dom ´ı nguez, E.; Tellitu, I. Chem.sEur. J 2007, 13, 5100.
4 2
, CuI, or CuCl with L3 afforded the N-arylated
(
(
9) For overviews, see: (a) Karayannis, N. M. Coord. Chem. ReV. 1973,
1
1, 93. (b) Albini, A. Synthesis 1993, 263.
of Cu(OAc)
2
, Cu
2
O, and CuClO
4
resulted in lower yields of
Org. Lett., Vol. 11, No. 15, 2009
3295

better than the others including K
2 3 3 4
CO , K PO , and KOH
(
Table 1, entries 8, 9, and 10). Control experiments confirmed
Table 2. N-Arylation of Imidazole with Aryl Halides Catalyzed
by CuSO /L3 in Water
4
that no product was detected in the absence of copper salt,
while only 9% yield was obtained by using copper sulfate
as catalyst (Table 1, entries 11 and 12). Furthermore, addition
a
4
of phase-transfer reagents such as (n-Bu) NBr into the
catalytic system seemed to have no positive effect on the
result (Table 1, entry 18). Temperatures lower than 120 °C
will dramatically decrease the reaction rate and entire
conversion (Table 1, entry 19). In summary, the optimal
conditions for the N-arylation process in water consist of
the combination of CuSO
4
(10 mol %), L3 (20 mol %), and
Cs CO (2 equiv) at 120 °C for 24 h in the air. The scope of
2
3
aryl halides was carried out by using imidazole as the
nucleophile. The results are listed in Table 2.
In general, most of the substituted aryl iodides and
electron-deficient aryl bromides afforded the N-arylimidazole
products with moderate to excellent yields ranging from 69%
to 95%. As usual, the coupling reaction between imidazole
and aryl iodides provided slightly superior yields than those
with aryl bromides, and aryl bromides bearing electron-
donating groups afforded much lower yields even with an
extended reaction time of 48 h (Table 2, entries 10 and 11).
It is noteworthy that the reaction was highly chemoselective;
for example, reaction between p-bromoiodobenzene and
imidazole gave 1-(4-bromophenyl)-1H-imidazole as the
major product (Table 2, entry 1).
Furthermore, the catalytic system exhibited tolerance with
aryl halides bearing nitrile, nitro, acetyl, ether, hydroxyl, or
amino groups without formation of diaryl ether, diarylamine,
or other coupling side products (Table 2, entries 5-7, 10,
1
2, and 13). Figure 2 shows the X-ray structure of the
coupling product 11 between imidazole and 4-bromoaniline.
Figure 2. X-ray structure of the coupling product 11.
In an endeavor to expand the scope of the methodology,
this new catalytic system was applied to a variety of
imidazole derivatives, and the results are shown in Table 3.
To our delight, most of the imidazole derivatives and
indoles exclusively afforded the corresponding products in
moderate to excellent yields (64-90%) under the optimized
reaction conditions. Notably, 2-methylimidazole could un-
dergo the selective N-arylation with 4-nitrobromobenzene
or 2-bromopyridine to afford corresponding coupling prod-
ucts in 85% or 72% yields (Table 3, entries 6 and 7). Another
a
Unless otherwise noted, the reactions were carried out with imidazole
CO (2.00 mmol), CuSO (10 mol
(
%
1.10 mmol), aryl halide (1.00 mmol), Cs
2
3
4
b
), and L3 (20 mol %) in water (3 mL) at 120 °C for 24 h. Determined by
GC/MS and confirmed by isolated yield after column chromatography. The
reaction time was 48 h.
c
1
6%, 12%, and 36% (Table 1, entries 15, 16, and 17).
Investigation of a variety of bases revealed that Cs CO was
2
3
3296
Org. Lett., Vol. 11, No. 15, 2009

and all of the coupling products were well characterized and
confirmed (see the Supporting Information).
Table 3. N-Arylation of Imidazoles with Aryl Halides Catalyzed
a
by CuSO
4
/L3 in Water
In summary, we have developed a simple, highly efficient,
economical, and environmentally friendly protocol for the
N-arylation of imidazoles with aryl iodides and bromides
promoted by a ligand-assisted copper catalyst in water. This
method avoids the use of toxic organic solvents and stringent
inert conditions. In addition, the catalytic system can be easily
4
generated using a mixture of the inexpensive CuSO and L3.
Overall, we believe that this catalytic system could provide
an avenue toward the Cu-catalyzed methods that have
scarcely been adopted in the aqueous phase. Further inves-
tigation to broaden the scope of this catalytic system to other
coupling reactions is currently ongoing in this laboratory.
Acknowledgment. This project was sponsored by the
Natural Science Foundation of China (Nos. 20672075,
2
0
0771076) and the Sichuan Provincial Foundation (08ZQ026-
41). We also thank the Analytic and Testing Centre of
Sichuan University for the NMR spectral determination.
Supporting Information Available: Synthetic procedures,
characterization, and X-ray crystallographic data. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
OL9010773
(
10) For recent examples and catalytic applications, see: Nienkemper,
K.; Kotov, V. V.; Kehr, G.; Erker, G.; Fr o¨ hlich, R. Eur. J. Inorg. Chem.
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2
(
(
a
Unless otherwise noted, the reaction was carried out with nitrogen
CO (2.00 mmol), CuSO
10 mol %), and L3 (20 mol %) in water (3 mL) at 120 °C for 24 h. Isolated
yield after column chromatography.
nucleophile (1.10 mmol), aryl halide (1.00 mmol), Cs
2
3
4
b
(
1
19, 3872. Angew. Chem., Int. Ed. 2007, 46, 3798. (j) Minakata, S.;
more bulkier N-nucleophile, 2-ethyl-4-methylimidazole, was
coupled with 2-bromopyridine to give 1-(2-pyridyl)-2-
methyl-4-ethylimidazole 19 in 64% yield (Table 3, entry 8),
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3297