A highly efficient Cu-catalyst system for N-arylation of azoles in water

Article abstract of DOI:10.1039/c2gc35077g

6,7-Dihydroquinolin-8(5H)-one oxime (L3) was found to serve as a superior ligand for the CuI-catalyzed N-arylation of imidazoles with aryl iodides, bromides, and electron-deficient chlorides in water. Moreover, the CuI/L3 catalyst system enabled the coupling reactions to take place smoothly with high yields under a low catalyst loading (0.1-1 mol% CuI and 0.2-2 mol% L3).

Full text of DOI:10.1039/c2gc35077g

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COMMUNICATION
A highly efficient Cu-catalyst system for N-arylation of azoles in water†
Deping Wang,*a Fuxing Zhang,a,b Daizhi Kuang,*a,b Jiangxi Yua,b and Junhua Lia,b
Received 16th January 2012, Accepted 23rd February 2012
DOI: 10.1039/c2gc35077g
formation (Fig. 1, L1 and L4),5a,b,10,12 but the conformationally
6,7-Dihydroquinolin-8(5H)-one oxime (L3) was found to
constrained 6,7-dihydroquinolin-8(5H)-one oxime (Fig. 1, L3)
has never been reported as a ligand. Herein, we wish to report
6,7-dihydroquinolin-8(5H)-one oxime, one of the commercially
available oximes, as an excellent ligand for the Cu-catalyzed N-
arylation of azoles with aryl iodides, bromides, and electron-
deficient chlorides in water. This protocol contains several
advantages: (1) water, an environmentally benign solvent, is
used in place of volatile organic solvents; (2) the coupling reac-
tions could take place with low catalyst loading (0.1 mol% CuI
and 0.2 mol% ligand for aryl iodides; 1 mol% CuI and 2 mol%
ligand for aryl bromides); (3) the catalyst system worked well for
aryl iodides, bromides, and electronic-withdrawing aryl chlorides
with good to excellent yields; (4) NaOH, a more inexpensive
base, is used for the coupling reaction.
Initially, we chose the coupling of bromobenzene with imida-
zole in water under a low catalyst loading (1 mol% CuI and
2 mol% Ligand) to identify the efficiency of various oximes
(Fig. 1). To our delight, L3 afforded the highest yield (95%)
under the specified conditions. Using L3 as ligand, the potential
catalytic efficiency of several other copper salts was
serve as a superior ligand for the CuI-catalyzed N-arylation
of imidazoles with aryl iodides, bromides, and electron-
deficient chlorides in water. Moreover, the CuI/L3 catalyst
system enabled the coupling reactions to take place smoothly
with high yields under a low catalyst loading (0.1–1 mol%
CuI and 0.2–2 mol% L3).
N-Arylazoles are important building blocks in numerous agro-
chemicals, pharmaceuticals, biological active compounds, and
N-heterocyclic carbene chemistry.1,2 Traditional synthetic
methods for these compounds3 often suffer from several draw-
backs such as harsh reaction conditions (>200 °C), the use of
stoichiometric amounts of copper reagents, and low functional-
group tolerance. Recently, Buchwald et al.4 and Taillefer et al.5
found several N- and O-based chelators which were highly
efficient ligands for the copper-catalyzed N-arylation of azoles.
After the discovery of these ligands, different mono- and biden-
tate ligands have been reported to promote the Cu-catalyzed N-
arylation of azoles under milder conditions.6 Nevertheless, there
is still a need to explore efficient catalytic systems, especially the
simple and eco-friendly catalytic systems.6j,7
As we all know, water is the most economical and eco-friendly
media in the world,8 and the wide use of N-arylazoles in many
fields have stimulated much interest into the development of new
methods for their synthesis in water. Recently, Zhou et al.9 and
Fu et al.10 reported several efficient ligands for the copper-cata-
lyzed N-arylation of imidazoles with aryl iodides and activated
aryl bromides in water. Wan et al. developed a Cu-additive
system for the coupling reactions of imidazoles with aryl iodides
and bromides in good yields in water, but in which the three
component catalyst system of 5 mol% CuO, 50 mol% oxalyldi-
hydrazide, and 100 mol% hexane-2,5-dione was essential.11
Thus, the coupling of electron-rich aryl bromides and aryl chlor-
ides with imidazoles in water remains problematic work for the
Cu-catalyst system.
On the other hand, oximes have been found to be efficient
ligands for the Cu-catalyzed C–C, C–N, and C–O bond
aDepartment of Chemistry and Material Science, Hengyang Normal
University, People’s Republic of China. E-mail: wdping0119@
gmail.com; Fax: +86-7348486629
bKey Laboratory of Functional Organometallic Materials of Hengyang
Normal University, College of Hunan Province, Hengyang 421008,
People’s Republic of China. E-mail: hnkdz@yahoo.com.cn
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc35077g
Fig. 1 Effect of ligands and copper salts on the efficiency of the N-ary-
lation of imidazole.
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Table 1 Cu/L3-catalyzed N-arylation of imidazole with aryl and
Table 1 (Contd.)
heteroaryl halides in watera
Entry
24
Ar–X
Product
Yieldb (%)
72
Entry
1
Ar–X
Product
Yieldb (%)
95
a Reaction conditions: Ar–X (4.0 mmol), imidazole (6.0 mmol), CuI
(1 mol%), L3 (2 mol%), nBu4NBr (10 mol%), NaOH (6.0 mmol), H2O
(3.0 mL), 120 °C, under N2, 48 h. b Isolated yield. c CuI (0.1 mol%), L3
(0.2 mol%). d NaOH (10 mmol). e CuI (5.0 mol%), L3 (10 mol%),
130 °C. f Without L3. g Without CuI and L3.
2
3
4
90c
93
94
5
6
95
93
subsequently evaluated (Fig. 1). The results showed that copper
compounds in I oxidation states were more catalytically active
and CuI gave the best result. Control experiments revealed that
no product was isolated in the absence of either the ligand or the
copper salt. In addition, a 63% yield of 1-phenyl-1H-imidazole
was achieved without nBu4NBr. Thus, the combination of 1 mol
% CuI, 2 mol% L3, 10 mol% nBu4NBr, and 150 mol% NaOH
in water was chosen as the optimal conditions for further
exploration.
7
8
9
91
90
87
As summarized in Table 1, the optimized conditions were
then applied to a wide range of substituted aryl iodides, bro-
mides, and chlorides. The results showed that excellent yields
were obtained for the coupling of aryl iodides with imidazole
(Table 1, entries 1–3). Also, we were pleased to find that only
0.1 mol% CuI and 0.2 mol% L3 could successfully arylate imi-
dazole with iodobenzene in 90% isolated yields (Table 1, entry
2). It is worth noting that no Cu–ligand system for C–N bond
formation in water has previously been reported to achieve 1000
turnovers. Various aryl bromides, including electron-rich, elec-
tron-neutral and electron-deficient aryl bromides, were coupled
with imidazole in excellent yields (Table 1, entries 4–17). Of
particular note, electron-rich aryl bromides have been considered
as highly challenging substrates for the Cu-catalysed N-arylation
of imidazoles in water.9,10 The CuI/L3 system was found to
effectively arylate imidazole with electron-rich aryl bromides in
water with 1 mol% CuI and 2 mol% L3 (Table 1, entries 8–15).
Furthermore, various functional groups, such as ketones, nitriles,
free amines, and free hydroxyls were well tolerated with satisfac-
tory yields under the optimal conditions (Table 1, entries 4, 5,
13–16).
10
11
83
90
12
61
13
14
15
78
82d
79
16
17
80
92
18
19
69e
21f
0g
40e
Attempts to use electron-deficient aryl chlorides to couple
with imidazole under catalyst loadings of 5 mol% CuI and
10 mol% L3 in water were successful and gave the desired pro-
ducts in moderate yields (Table 1, entries 18–20). To the best of
our knowledge, there are no previous examples of the Cu-cata-
lyzed synthesis of N-arylimidazoles directly from aryl chlorides
in water.13 While 1-chloro-4-nitrobenzene coupled with imida-
zole, without L3 or both CuI and L3, the yield was dramatically
reduced to 21% and 0%, respectively (Table 1, entry 18).
However, when chlorobenzene was used as the substrate, no
coupling products were isolated (Table 1, entry 21). Moreover,
the reactions of various bromopyridines with imidazole were
20
21
22
33e
0
94
23
90
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Table 2 Cu/L3-catalyzed N-arylation of azoles with aryl halidesa
Entry
1
Ar–X
Product
Yieldb (%)
90
2
3
77
68
4
5
33c
86
Scheme 1 Proposed mechanism.
In summary, we have developed an excellent copper catalytic
system for the arylation of N–H heterocycles with 6,7-dihydro-
quinolin-8(5H)-one oxime as ligand in water. This N-arylation
process takes place under a low catalyst loading (0.1–5 mol%
CuI) and avoids the use of expensive bases. Overall, we believe
that this economical, general, and highly efficient method could
provide an attractive complement to the Cu-catalyzed synthesis
of N-arylazoles.
6
7
83
75
a Reaction conditions: Ar–X (4.0 mmol), imidazole (6.0 mmol), CuI
(1 mol%), L3 (2 mol%), NaOH (6.0 mmol), nBu4NBr (10 mol%), H2O
(3.0 mL), 120 °C, under N2, 48 h. b Isolated yield. c CuI (5.0 mol%), L3
(10 mol%), 130 °C.
Acknowledgements
We thank the Scientific Research Foundation of Hengyang
Normal University (no. 11B39) for financial support.
also performed with great success. Almost all the bromopyri-
dines coupled with imidazole in excellent yields in water
(Table 1, entries 22–24).
Notes and references
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CuI/L3 system was explored with other nitrogen-containing het-
erocycles. As listed in Table 2, a variety of five-membered
azoles such as 1,2,4-triazole, benzimidazole, and pyrazole
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2-propylimidazole coupled with aryl bromides in good yields
(Table 2, entries 2, 3, and 7). N-arylation of benzimidazole and
4-methyl-1H-pyrazole with aryl bromides bearing a nitrile and a
free amino group could successfully take place to assemble the
corresponding products in yields of 86% and 83%, respectively
(Table 2, entries 5–6).
Based on previous literature reports,4e,5b,6e a possible mechan-
ism of the Cu/L3-catalyzed N-arylation of N–H heterocycles is
proposed in Scheme 1. The chelating Cu(I) with L3 formed a
six-member reactive species I, and the subsequent oxidative
addition of I with aryl halides produced the transient CuIII species
II. In the presence of base, the intermediate II was nucleophilic
substituted by N–H heterocycles to afford intermediate III, fol-
lowed by reductive elimination readily to provide the coupling
product and regenerate the active Cu(I) species I.
1270 | Green Chem., 2012, 14, 1268–1271
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