Sulfonato-Cu(salen) complex catalyzed N-arylation of aliphatic amines with aryl halides in water

Article abstract of DOI:10.1002/ejoc.201000840

A water-soluble sulfonato-Cu(salen) complex catalyzed procedure for the N-arylation of simple aliphatic amines, amino alcohols and amino acids in pure water have been developed. A variety of substituted aryl iodides, bromides and electron-deficient chlorides were found to be applicable, and 1,2-disubstituted benzimidazoles could be prepared easily by a cascade amination/condensation process in this catalytic system.

Full text of DOI:10.1002/ejoc.201000840

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000840
Sulfonato–Cu(salen) Complex Catalyzed N-Arylation of Aliphatic Amines with
Aryl Halides in Water
Zhiqing Wu,[a] Li Zhou,[a] Zhaoqiong Jiang,[a] Di Wu,[a,b] Zhengkai Li,[a] and
Xiangge Zhou*[a,b]
Keywords: Copper / Cross-coupling / Sulfonates / Amination / Water chemistry
A water-soluble sulfonato-Cu(salen) complex catalyzed pro-
cedure for the N-arylation of simple aliphatic amines, amino
alcohols and amino acids in pure water have been devel-
oped. A variety of substituted aryl iodides, bromides and
electron-deficient chlorides were found to be applicable, and
1,2-disubstituted benzimidazoles could be prepared easily by
a cascade amination/condensation process in this catalytic
system.
Therefore, there has been increased interest in catalytic
cross-coupling reactions in aqueous medium by water-solu-
ble transition metal complexes recently.[16,17] On the other
hand, salen ligands and related transition metal complexes
are well known for enabling a broad array of organic trans-
formations. However, it is rarely used in Ullmann-type
cross-coupling reactions to date. In 2004, Taillefer and co-
workers described an efficient copper-catalyzed N-arylation
of heterocycles with aryl halides under mild conditions sup-
ported by tetradentate Schiff base ligands in an organic me-
dium.[18] Inspired by this pioneering work, we have recently
prepared a water-soluble sulfonato–Cu(salen) complex,
which was successfully applied in the catalytic N-arylation
of imidazoles and aqueous ammonia with aryl halides in
water without an inert gas.[19] Encouraged by these pre-
cedents, we envisioned such catalyst may be applied in other
types of C–N bond-forming processes. Thus, a series of ali-
phatic N-nucleophiles including simple aliphatic amines,
amino alcohols and amino acids was employed to react
with aryl halides in water. Herein, we wish to disclose the
results.
Introduction
The copper-catalyzed C–N bond formation by the
pioneering work of Ullmann and Goldberg has became one
of the most powerful synthetic strategies for the construc-
tion of nitrogen-containing intermediates, which are key
structural motifs for the synthesis of pharmaceuticals, agro-
chemicals, polymers, or materials.[1] Over the past decade,
many efforts have been devoted to this methodology to im-
prove its efficiency and selectivity by demonstrating the use
of chelating ligands,[2] including 1,3-diketones,[3] 1,2-di-
amines,[4] phenanthrolines,[5] bipyridines,[6] α-amino acids,[7]
diols,[8] salicylamides[9] and others.[10] Recently, Buchwald
and Hartwig and co-workers made significant progresses in
the mechanism study of diamine ligands promoted
Ullmann-type C–N cross coupling.[11] Although important
advances have been made in the aforementioned transfor-
mations, it is still highly desired to develop readily available,
economic and environmentally friendly protocols for this
type of reactions.
In general, organic solvents are used extensively for or-
ganic transformations, which lead to various environmental
and health concerns.[12] Considering the requirement of
green chemistry, various cleaner solvents have been evalu-
ated as replacement, such as water,[13] supercritical fluids[14]
and ionic liquids.[15] As a natural solvent, the nontoxic,
cheap, and readily available water is obviously the most at-
tractive one for both academic and industrial settings.
Results and Discussion
Our first effort was devoted to the preparation of a vari-
ety of substituted sulfonato–Cu(salen) complexes as indi-
cated in Figure 1. Complexes 1–6 could be conveniently
synthesized by condensation of the corresponding diamines
with 5-sulfonatosalicylaldehydes and a sequential addition
of copper acetate in good yields.
To evaluate the catalytic efficiency of the catalyst, 4-iodo-
toluene and cyclohexylamine were chosen as model sub-
strates for the reaction catalyzed by copper complex
(10 mol-%) in the presence of NaOH (2 equiv.) in water at
120 °C as shown in Table 1. Gratifyingly, the substrates
were transformed into the desired N-arylated products in
View this journal online at
[a] Institute of Homogeneous Catalysis, College of Chemistry,
Sichuan University,
Chengdu 610064, China
Fax: +86-28-85412026
E-mail: zhouxiangge@scu.edu.cn
[b] State Key Laboratory of Coordination Chemistry, Nanjing
University,
Nanjing 210093, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000840.
wileyonlinelibrary.com
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Z. Wu, L. Zhou, Z. Jiang, D. Wu, Z. Li, X. Zhou
SHORT COMMUNICATION
Table 1. Optimization of sulfonato–Cu(salen) complex catalyzed
cross coupling between 4-iodotoluene and cyclohexylamine in
water.[a]
Entry Catalyst (mol-%)
Base
T [h] Yield [%][b]
1
2
3
4
5
1 (10)
2 (10)
3 (10)
4 (10)
5 (10)
6 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (5)
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
–
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
9
79
70
80
77
40
41
52
41
79
79
81
81
43
47
42
62
89
88
89
70
trace
6
7[c]
8
9
Na2CO3
K2CO3
Cs2CO3
K3PO4
CH3COONa
NaHCO3
N(Et)3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
10
11
12
13
14
15
16
17
18
19[d]
20
21
Figure 1. Structures of sulfonato–Cu(salen) complexes 1–6.
15
20
15
15
15
comparable moderate yields ranging from 70 to 80% in the
presence of complexes 1–4, which indicates that the substit-
uents of the benzene ring have only a small effect on the
catalysis (Table 1, Entries 1–4). However, when the diamine
was changed from diaminobenzene to diaminocyclohexane
or 1,2-ethylenediamine, the yields dropped dramatically to
around 40% (Entries 5–6). Thus, complex 1 was selected as
catalyst in the following studies. The temperature was a key
–
[a] Unless otherwise noted, the reaction was carried out with 4-
iodotoluene (0.5 mmol), amine (2 mmol), and base (1 mmol) in
water (2 mL) at 120 °C. [b] Isolated yields. [c] Performed at 100 °C.
[d] nBu4NBr (20 mol-%) was added as PTC.
parameter in the process, and attempts to lower it resulted tively (Table 2, Entries 3 and 6). Notably, sterically de-
in a decreased yield (Table 1, Entry 7). Furthermore, the manding ortho substituents did not hamper the arylation
base is another important factor for the N-arylation reac- reaction (Table 2, Entries 8 and 9). Heterocyclic aryl halides
tion; a control experiment showed that the yield decreased could also be coupled with cyclohexylamine to afford the
to 41% in the absence of any base (Table 1, Entry 8). The corresponding products in excellent yields (Table 2, En-
following base screening showed that Na2CO3, K2CO3, tries 10 and 11). Then, we were intrigued by the possibility
Cs2CO3, K3PO4 and NaOH were all effective and gave quite of using the aryl chlorides as coupling partner, which have
similar results; CH3COONa, NaHCO3 and organic bases been proven to be problematic substrates in Ullmann-type
such as triethylamine resulted in lower yields (Table 1, En- cross couplings. To our pleasure, several electron-deficient
tries 9–15). Moreover, the extension of the reaction time to aryl chlorides afforded the corresponding products in mod-
15 h improved the yield to 89% (Table 1, Entries 16–18). erate yields (Table 2, Entries 3 and 11). 2-chlorobenzoic
The addition of phase-transfer catalysts (PTCs) seemed to acid also exhibited a high activity due to the possible ortho-
be not necessary in this case with almost the same result substituent effect, which might greatly expand the applica-
(Table 1, Entries 17 and 19). Test experiments carried out tion of this methodology (Table 2, Entry 12).[20]
in the absence of catalyst led to trace yields of the desired
In order to expand the scope of the catalysis, a series
product, which illustrates the key role of the water-soluble of aliphatic N-nucleophiles was employed to react with 4-
sulfonato–Cu(salen) complexes in this transformation iodotoluene. As shown in Table 3, all the examined linear
(Table 1, Entry 21).
and branched aliphatic amines afforded the corresponding
Next, a variety of aryl halides were tested under the opti- N-arylated products in good to excellent yields (Table 3,
mized reaction conditions. As shown in Table 2, all the aryl Entries 1–6). Notably, amino alcohols selectively form the
iodides and most of the bromides reacted with cyclohex- N-arylated product with satisfactory yield, which is of great
ylamine smoothly, leading to the desired products in mod- interest in medicinal chemistry (Table 3, Entry 7).[21]
erate to excellent yields. Electron-withdrawing groups
Among numerous functionalized amines, the ubiquitous
seemed to be a little beneficial for the catalysis compared amino acids and their derivatives are important chemical
to electron-donating ones. For example, 1-bromo-4-nitro- building blocks in organic and biological chemistry.[22]
benzene and 1-bromo-4-methoxybenzene led to the corre- Therefore, the N-arylation of amino acids has attracted
sponding arylated products in 90% and 85% yields, respec- much attention in recent years.[23] In this work, both α- and
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Eur. J. Org. Chem. 2010, 4971–4975

N-Arylation of Aliphatic Amines with Aryl Halides in Water
Table 2. N-arylation of cyclohexylamine with aryl halides in water
catalyzed by sulfonato–Cu(salen) complex 1.[a]
Table 3. N-Arylation of aliphatic amines with 4-iodotoluene in
water catalyzed by sulfonato–Cu(salen) complex 1.[a]
[a] Reaction conditions: 4-iodotoluene (0.5 mmol), amine
(2 mmol), catalyst 1 (10 mol-%), base (1 mmol), H2O (2 mL),
120 °C, 15 h. [b] Isolated yields.
Scheme 1. N-Arylation of amino acids in water catalyzed by
sulfonato–Cu(salen) complex 1.
[a] Reaction conditions: aryl halide (0.5 mmol), amine (2 mmol),
catalyst 1 (10 mol-%), base (1 mmol), H2O (2 mL), 120 °C, 15 h.
[b] Isolated yields. [c] Without catalyst.
β-amino acids could be employed as coupling partner to
give good yields as shown in Scheme 1.
Furthermore, 1,2-disubstituted benzimidazoles are im-
portant heterocycles found in a variety of natural products
and exhibit a wide range of biological properties.[24] Al-
though a variety of synthetic methods for the synthesis of
these important frameworks has been developed, exploring
of straightforward and general methods for the synthesis of
1,2-disubstituted benzimidazoles from easily available pre-
cursors is still in demand.[25] Recently, we have demon-
strated that substituted 1H-benzimidazole could be easily
prepared by a cascade amination/condensation process in
the presence of sulfonato–Cu(salen) complex 1.[19b] Subse-
Scheme 2. Synthesis of 1,2-disubstituted benzimidazoles in water.
Conclusions
We have developed a simple and efficient catalytic N-
quent to this discovery, we discovered that the 1,2-disubsti- arylation protocol of aliphatic amines promoted by an inex-
tuted benzimidazoles could also be prepared by utilizing pensive water-soluble sulfonato–Cu(salen) complex in pure
this catalytic protocol; both 2-iodoacetanilide and 2-bro- water. The environmentally benign process contains several
moacetanilide were applicable as substrates (Scheme 2).
noteworthy features, including: (1) the protocol utilizes the
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SHORT COMMUNICATION
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N-nucleophiles, including simple aliphatic amines, amino
alcohols and amino acids provided high selectivity with
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[11]
General Procedure for the N-Arylation of Amino Acids in Water:
Catalyst (0.05 mmol), aryl halide (0.5 mmol), NaOH (2 mmol),
amino acid (1 mmol) and water (2 mL) were added to a sealed tube.
The reaction mixture was stirred at 120 °C for 20 h and then cooled
to room temperature. 2  HCl was added to adjust the pH to 3,
and then extracted with ethyl acetate. The organic layer was dried
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Supporting Information (see footnote on the first page of this arti-
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Acknowledgments
C. M. Gordon, W. Leitner, Catalyst Separation Recovery and
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This project was financially sponsored and supported by the
National Natural Science Foundation of China (Nos. 20672075,
20771076, 20901052), the Sichuan Provincial Foundation
(08ZQ026-041) and the Ministry of Education (NCET-10-0581).
We also thank the Analysis and Testing Center of Sichuan Univer-
sity for NMR measurements.
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Received: June 10, 2010
Published Online: August 16, 2010
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