Facile and efficient amination of organic halides catalyzed by copper sulfate in PEG1000-DIL/methylcyclohexane temperature-dependent biphasic system

Article abstract of DOI:10.1002/jccs.201000084

A simple, efficient, and environmentally friendly procedure for the amination of organic halides catalyzed by CuSO₄·5H ₂O in PEG₁₀₀₀-DIL/methylcyclohexane temperature-dependent biphasic system is described. The product can be easily isolated by a simple decantation, and the catalytic system can be recycled and reused without loss of catalytic activity.

Full text of DOI:10.1002/jccs.201000084

604
Journal of the Chinese Chemical Society, 2010, 57, 604-611
Communication
Facile and Efficient Amination of Organic Halides Catalyzed by Copper
Sulfate in PEG1000-DIL/Methylcyclohexane Temperature-dependent
Biphasic System
Yu-Lin Hua (
Tian Chenb (
), Peng-Cheng Wanga (
) and Ming Lua* (
),
)
aCollege of Chemical Engineering, Nanjing University of Science and Technology,
Nanjing 210094, P. R. China
bCollege of Material Science and Technology, Nanjing University of Aeronautics and Astronautics,
Nanjing 210016, P. R. China
A simple, efficient, and environmentally friendly procedure for the amination of organic halides cata-
lyzed by CuSO4·5H2O in PEG1000-DIL/methylcyclohexane temperature-dependent biphasic system is de-
scribed. The product can be easily isolated by a simple decantation, and the catalytic system can be recy-
cled and reused without loss of catalytic activity.
Keywords: Amination; Organic halide; Copper sulfate; PEG1000-DIL; Thermoregulated ionic
liquid biphasic system.
INTRODUCTION
of atom economy, since they generate large amounts of
solid waste and also require a stoichiometric amount of
base. Copper mediated N-arylation is another choice of re-
action for the production of these compounds due to cheap
price and environmental friendly nature. Therefore, cop-
per-based protocols are powerful methods for coupling of
aryl halides and amines and attract a great attention, which
make the reactions of choice in large and industrial scale
applications. Especially, copper-based Ullmann-type reac-
tions are often successful where palladium-based proce-
dures have failed.21 A variety of copper reagents, such as
Cu2O,22 Cu,23 CuX,24-26 CuX2,27-28 Cu(OAc)2,29 Cu-CuX,30,31
copper complexes,32,33 and other systems,34-36 have been
developed for this conversion. However, these procedures
are still invariably associated with a complexity of using a
solid base, expensive and often sensitive ligands are neces-
sary to activate themetal center and to stabilize the complex
during the reaction, and difficulties in recycling of the cata-
lyst. As a consequence, the development of an environmen-
tally benign procedure for addressing these drawbacks re-
mains an impending goal.
Amines and their derivatives are important organic
chemicals commonly encountered in biologically relevant
natural or synthetic pharmaceutical compounds, in xero-
graphic and photographic materials or in conducting poly-
mers.1,2 Therefore, there has been tremendous interest in
developing efficient methods for the synthesis of these
molecules, and a well known method constitutes the amina-
tion of aryl halides. The amination of aryl halides by transi-
tion metal catalyzed coupling methodology has been the
subject of significant interest during past few decades.3,4
This method involves production of arylamines by cou-
pling of aryl halides and amines with stoichiometric amount
of transition metal ions. Traditionally, the most common
way to access these compounds is palladium-catalyzed
C–N coupling of amines and aryl halides.5-12 However, the
cost of reagents, removal of trace palladium from late stage
synthetic intermediate, and difficulties in coupling of elec-
tron-rich or ortho-substituted aryl halides are the major
drawbacks of this method. In addition to palladium cata-
lysts, rhodium,13-16 and nickel17-20 transition metal catalysts
have been developed for N-arylation of aryl halides with
amines, however, these methods have drawbacks in terms
Ionic liquids (ILs) have recently gained recognition
as environmentally benign alternative solvents for analyti-
* Corresponding author. Tel: +86-025-84315030; Fax: +86-025-84315030; E-mail: luming1963@163.com

Amination of Organic Halides
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 605
cal and separation science,37 chemical synthesis,38,39 elec-
trochemistry,40 and catalysis.41 In view of both the advan-
tages and disadvantages of homogeneous and heteroge-
neous catalysts, and to improve catalyst recovery, multi-
phase systems, such as phase-transfer catalysis,42,43 ther-
moregulated phase transfer catalysis,44 and liquid-liquid
biphasic catalysis,45 have been studied. Some novel tem-
perature-dependent ionic liquid biphasic catalytic systems
have been reported recently,46-48 and in our research project
group, Luo and co-workers reported a new PEG1000-based
dicationic ionic liquid exhibiting temperature-dependent
phase behavior with toluene recently and had applied it in
the acetalization of aromaldehyde and ethyleneglycol suc-
cessfully.49 They found that the IL showed some advan-
tages such as high conversions and selectivity, stability at
high temperatures, reusability in the reaction, etc, which
provide a novel route for the separating and recycling of
catalysts.
Table 1. Optimization of the conditions for amination of of
chlorobenzene with aqueous ammoniaa
Entry Ionic liquid
Catalyst
Time (h)
Yield (%)b
1
¾
¾
24
06
06
06
06
10
12
06
06
06
06
06
06
12
16
00
81
84
90
93
67
45
87
80
84
89
86
83
52
58
2
PEG400-DIL
PEG600-DIL
PEG800-DIL
PEG1000-DIL
¾
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
¾
3
4
5
6
7
PEG1000-DIL
PEG1000-DIL
PEG1000-DIL
PEG1000-DIL
PEG1000-DIL
PEG1000-DIL
8
CuCl2
CuCl
CuBr
CuI
9
10
11
12
13
14
15
FeSO4
PEG1000-DIL Cu(OAc)2
PEG1000-DIL
PEG1000-DIL
MnSO4
Cu2O
a The reactions were carried out with chlorobenzene (1 mmol),
28% NH3·H2O (1.1 mmol), catalyst (0.5 mmol), PEG-DIL (3
mL), in methylcyclohexane (3 mL) at 60 °C. b Isolated yield.
Here, we report a facile, efficient and environmen-
tally friendly protocol for the amination of organic halides
with aqueous ammonia or amines catalyzed by copper sul-
fate (CuSO4·5H2O) in the PEG1000-based dicationic ionic
liquid (PEG1000-DIL) under mild conditions (Scheme I).
We found that the PEG1000-DIL/methylcyclohexane tem-
perature-dependent biphasic system is active for the amina-
tion and that it is an environmentally conscious catalytic
system.
tested with CuSO4 as catalyst in the reaction (Table 1, en-
tries 2-5), it was observed that PEG1000-DIL demonstrated
the best performance (Table 1, entry 5). The different ef-
fects of ILs may be attributed to their different abilities of
forming a homogeneous catalysis by exhibiting a tempera-
ture-dependent phase behavior with methylcyclohexane,
the IL who forms the homogeneous catalysis more easily
will leads to a larger increase in the effective reactant con-
centration, and the higher reaction rate or yield is observed.
As expected, no product was detected in the absence of
ionic liquid and catalyst (Table 1, entry 1). The catalyst
CuSO4 and ionic liquid PEG1000-DIL are crucial for the
amination, and the lack of any component can lead to a
much lower yield (Table 1, entries 6 and 7). Furthermore,
several simple catalyst precursors were also examined,
CuSO4, CuCl2, CuCl, CuBr, CuI, Cu(OAc)2, and FeSO4
were all effective for the transformation (Table 1, entries 5
and 8-13), and CuSO4 was proved to be the best catalyst.
On the otherhand, a much lower yield was obtained when
either MnSO4 or Cu2O was used (Table 1, entries 14 and
15). Thus, CuSO4 was selected as the catalyst in the follow-
ing studies.
Scheme I
RESULTS AND DISCUSSION
In addition, the catalytic system could be typically re-
covered and reused for subsequent reactions with no appre-
ciable decrease in yields and reaction rates (Fig. 1). The re-
cycling process involved the removal of the upper layer of
To optimize the reaction conditions, chlorobenzene
and aqueous ammonia were firstly chosen as the model
substrates (Table 1). Four type of ionic liquids, PEG400
-
DIL, PEG600-DIL, PEG800-DIL, and PEG1000-DIL, were

606 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Hu et al.
ides, especially those with electron-withdrawing substitu-
ents (Table 2, entries 4-6, 9 and 11), were more reactive
than those with or without electron-donating substituents
(Table 2, entries 1-3, 7, 8, 10 and 12), provided excellent
yields. It was also observed that the reactions are faster
with benzylic or allylic halides (Table 2, entries 15-21) than
with aryl halides (Table 2, entries 1-12). In addition, in or-
der to examine a greater range of amines to better illustrate
the scope and limitations of the method, we investigated
the reactions with primary and secondary amines such as
n-butylamine, cyclohexylamine, pyrrolidine, N-methylan-
iline, morpholine, and piperidine using bromobenzene as a
representative organic halide (Table 2, entries 22-27), ex-
cellent yields of the expected amines were obtained.
Fig. 1. Repeating reactions using recovered catalytic
system. The reactions were carried out with
chlorobenzene (1 mmol), 28% NH3·H2O (1.1
mmol), recovered catalytic system (PEG1000
-
The excellent reaction results of the catalytic system
suggest that the amination among organic halides, aqueous
ammonia or amines, CuSO4·5H2O, methylcyclohexane and
PEG1000-DIL has a particular catalytic process, which is
schematically depicted in Fig. 2. Before the amination,
there exists an obvious biphasic system, and the under layer
consists of PEG1000-DIL, CuSO4·5H2O and aqueous ammo-
nia (primary and secondary amines exist in the upper layer),
the upper layer consists of methylcyclohexane and sub-
strates. During the process of ammonia, the biphasic sys-
tem disappeares and a homogeneous reaction medium is
formed. After the reaction, a complete phase-separation is
formed again after being cooled to room temperature, the
next process involved the removal of the upper layer of
methylcyclohexane, containing product, by decantation
and concentration of the under layer of catalytic system.
Fresh subtrates and methylcyclohexane were then re-
charged to the residual catalytic system and then recycle.
The PEG1000-DIL plays a very important role in the ammo-
DIL and CuSO4·5H2O), in methylcyclohexane
(3 mL) at 60 °C for 6 h.
methylcyclohexane, containing product, by decantation
and concentration of the under layer of catalytic system by
removing the water under vacuum. Fresh subtrates and
methylcyclohexane were then recharged to the residual
PEG1000-DIL and the mixture was heated to react once
again.
The catalytic amination of a wide variety of organic
halides with aqueous ammonia, primary and secondary
amines was successful and gave the desired products in
good to excellent yields as summarized in Table 2. Various
types of aryl, benzylic, allylic, and aliphatic halides can be
successfully aminolyzed to the corresponding primary ani-
lines with aqueous ammonia (Table 2, entries 1-21), where-
as the aliphatic halides were less reactive, higher reaction
temperature and longer reaction time were needed to reach
good yields (Table 2, entries 13 and 14). All the aryl hal-
Fig. 2. Thermoregulated ionic liquid biphase catalytic process for the ammonia.

Amination of Organic Halides
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 607

608 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Hu et al.

Amination of Organic Halides
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 609
nia process to locally concentrate the reacting species near
them by exhibiting a temperature-dependent phase behav-
ior with methylcyclohexane (i.e. the thermoregulated bi-
phasic behavior of mono-phase under high temperature and
bi-phase under room temperature), which leads to a large
increase in the effective reactant concentration and the ex-
cellent results of ammonia.
are uncorrected. High performance liquid chromatography
(HPLC) experiments were performed on a liquid chro-
matograph (Dionex Softron GmbH, America), consisting
of a pump (P680) and ultraviolet-visible light detector
(UVD) system (170U). The experiments were performed
on Diacovery C18 column, ø 4.6 ´ 250 mm. Elemental
analysis were performed on a Vario EL III instrument
(Elmentar Anlalysensy Teme GmbH, Germany).
CONCLUSIONS
General procedure for ammonia reactions
In conclusion, we have developed a simple, highly ef-
ficient, and environmentally friendly protocol for the ami-
nation of organic chlorides catalyzed by CuSO4·5H2O in
PEG1000-DIL/methylcyclohexane temperature-dependent
biphasic system. Awide range of aryl, benzylic, allylic, and
aliphatic halides were found to be applicable to the cata-
lytic system. Advantages of our procedure include mild re-
action conditions, simplicity of operation, high yields, easy
isolation of products, good thermoregulated biphasic be-
havior of the IL, and excellent recyclability of the catalytic
system. The definition of the mechanism and the applica-
tion of the environmentally benign catalytic system to other
organic synthesis are currently under investigation.
Organic halide (1 mmol), CuSO4·5H2O (0.5 mmol),
aqueous ammonia or amine (1.1 mmol), PEG1000-DIL (3
mL), and methylcyclohexane (3 mL) were added to a round
bottom flask. The reaction mixture was stirred at 60 °C for
the appropriate time (Table 2), the reaction progress was
monitored by HPLC. The mixture was then cooled to room
temperature and the organic phase was separated by de-
cantation, and then rinsed with water (3 ´ 10 mL). The or-
ganic phase was dried with anhydrous sodium sulfate, fil-
tered, and the solvent was removed under reduced pres-
sure. The aniline product was finally obtained by column
chromatography on silica gel. The next run was performed
under identical reaction conditions. All the products were
1
confirmed by H NMR, Elemental analysis or compared
EXPERIMENTAL
with their authentic samples. Spectroscopic data for selected
products is as follows.
Apparatus and reagents
All the chemicals were from commercial sources
without any pretreatment. All reagents were of analytical
grade. The ionic liquids were synthesized according to the
literature procedure.49 1H NMR spectra were recorded on a
Bruker 400-MHz spectrometer using CDCl3 as the solvent
with tetramethylsilane (TMS) as an internal standard. Melt-
ing points were recorded on a Buchi R-535 apparatus and
N-Butylaniline (Table 2, entry 22)
Colorless liquid. 1H NMR (400 MHz, CDCl3): d 0.96
(t, J = 8.0 Hz, CH3, 3H), 1.39 (m, CH2, 2H), 1.57 (m, CH2,
2H), 3.07 (t, J = 8.0 Hz, CH2, 2H), 3.52 (br, NH, 1H), 6.62-
6.67 (m, Ar-H, 3H), 7.27 (m, Ar-H, 2H). Anal. Calcd for
C10H15N: C, 80.46; H, 10.12; N, 9.37. Found: C, 80.48; H,
10.13; N, 9.39.

610 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
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N-Cyclohexylaniline (Table 2, entry 23)
Colorless liquid. 1H NMR (400 MHz, CDCl3): d 1.16
(m, CH2, 2H), 1.34 (m, CH2, 4H), 1.83 (m, CH2, 4H), 3.19
(m, CH, 1H), 3.42 (br, NH, 1H), 6.59-6.64 (m, Ar-H, 3H),
7.14 (m, Ar-H, 2H). Anal. Calcd for C12H17N: C, 82.21; H,
9.78; N, 7.96. Found: C, 82.23; H, 9.78; N, 7.99.
N-Phenylpyrrolidine (Table 2, entry 24)
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Colorless liquid. 1H NMR (400 MHz, CDCl3): d 1.96
(m, CH2, 4H), 3.23 (t, J = 8.0 Hz, CH2, 4H), 6.56-6.64 (m,
Ar-H, 3H), 7.19 (m, Ar-H, 2H). Anal. Calcd for C10H13N:
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1
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CH2, 4H), 6.83-6.87 (m, Ar-H, 3H), 7.28 (m, Ar-H, 2H).
Anal. Calcd for C10H13NO: C, 73.56; H, 8.01; N, 8.59; O,
9.79. Found: C, 73.59; H, 8.03; N, 8.58; O, 9.80.
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4H), 6.83-6.91 (m, Ar-H, 3H), 7.22 (m, Ar-H, 2H). Anal.
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ACKNOWLEDGEMENTS
We thank the National Basic Research Program (973)
of China (No. 613740101) and Natural Science Foundation
of Jiangsu Province for support of this research.
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Received April 30, 2010.
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