A simple and recyclable copper/DTPA catalyst system for amination of aryl halides with aqueous ammonia in water

Article abstract of DOI:10.1016/j.catcom.2013.10.030

Commercially available CuO/DTPA (diethylenetriaminepentaacetic acid) was established to be a low-cost, recyclable, and environmentally benign homogeneous catalyst system for direct amination of aryl halides with ammonia. Primary aryl amines can be readily prepared from both electron-withdrawing and electron-donating aryl halides in good yields in water without the addition of surfactants.

Full text of DOI:10.1016/j.catcom.2013.10.030

A simple and recyclable Copper/DTPA catalyst system for amination of aryl
halides with aqueous ammonia in water
Bo Yang, Lihao Liao, Yongheng Zeng, Xinhai Zhu, Yiqian Wan
PII:
DOI:
Reference:
S1566-7367(13)00401-9
doi: 10.1016/j.catcom.2013.10.030
CATCOM 3690
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
30 August 2013
24 October 2013
24 October 2013
Please cite this article as: Bo Yang, Lihao Liao, Yongheng Zeng, Xinhai Zhu,
Yiqian Wan, A simple and recyclable Copper/DTPA catalyst system for amination
of aryl halides with aqueous ammonia in water, Catalysis Communications (2013), doi:
10.1016/j.catcom.2013.10.030
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ACCEPTED MANUSCRIPT
A simple and recyclable Copper/DTPA catalyst system for
amination of aryl halides with aqueous ammonia in water
Bo Yang, Lihao Liao, Yongheng Zeng, Xinhai Zhu,* and Yiqian Wan
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. of China
Tel: +86-2084113610
Fax: +86-2084113610
E-mail: zhuxinh@mail.sysu.edu.cn
Abstract: Commercially available CuO/DTPA (diethylenetriaminepentaacetic acid) was
established to be a low-cost, recyclable, and environmentally benign homogeneous catalyst system
for direct amination of aryl halides with ammonia. Primary aryl amines can be readily prepared
from both electron-withdrawing and electron-donating aryl halides in good yields in water without
addition of surfactants.
Keywords: Copper; Amination; Water; Homogeneous catalysis; recyclable
1. Introduction
Primary aryl amines are important compounds, having applications in the pharmaceutical,
agrochemical, dye, cosmetic and toiletry industries.[1, 2] As a result, the development of highly
efficient and environmentally benign methods for their synthesis has drawn increasing attention.[3]
Ammonia is an attractive source of nitrogen for the industrial production of organic amino
compounds due to its abundance and low cost.[4, 5] However, to avoid the formation of secondary
and tertiary amine by-products, early research in this area typically required the use of ammonia
surrogates as the source of nitrogen.[6-8]
Hartwig and co-workers reported Pd-catalyzed aniline formation from aryl halides and
ammonia in 2006, [9] and since then, many protocols for selective Pd-catalyzed amination of aryl
halides with ammonia have been published.[10-14] Later, Lang and co-workers developed
copper-catalyzed amination of aryl halides with ammonia at low pressures and low
temperatures,[15] allowing for lower cost synthesis as both the copper centers and their associated
ligands are less expensive when compared to Pd catalysts. Following this, copper-catalyzed
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procedures for the direct coupling of aryl halides with aqueous ammonia, gaseous ammonia or
liquid ammonia have been reported in mild conditions with good tolerance of a wide range of
functional groups.[16-27]
The protocols mentioned above are generally performed in organic solvents, most of which
are toxic and expensive. Although some alcoholic solvents could be regarded environmental
friendly, they are still flammable and not naturally occurring. As a result, there is a need to find a
procedure to carry out these coupling reactions in cheap, safe and environmentally benign solvent.
Recently, the copper-catalyzed C–N coupling reactions for the effective synthesis of aniline from
aryl halides and aqueous ammonia have been carried out in water. For example, Xu reported that
the amination of aryl iodides and bromides with NH3·H2O could be achieved in an aqueous
solution of nBu4NOH in the presence of CuI nanoparticles under a nitrogen atmosphere. [28] In
addition, we have reported copper/sucrose as a recyclable, green catalyst for the effective and
direct amination of aryl halides with NH3·H2O at 90 °C in an aqueous solution of PEG-200.[29]
However, requirement of a non-commercially available catalyst system [30-33] and/or large
amounts of surfactant (such as quaternary ammonium salt [32-34] or its base [28], PEGs [29, 35])
made these protocols less practical. Still there is a need to develop a more convenient, recyclable
catalyst for direct amination with ammonia in water.
Herein, we report commercially available copper/ DTPA (diethylenetriaminepentaacetic acid)
as an inexpensive, recyclable and environmentally benign, homogeneous catalyst system for the
coupling of aryl bromides and iodides with aqueous ammonia in water without any surfactant.
2. Experimental
2.1 Materials and Instrumentation
All starting materials and reagents are commercially available and used as received. All
reactions were carried out in a preheated oil bath in 10 mL vials sealed with septa. Flash column
chromatography was performed with silica gel (200-300 mesh). Thin-layer chromatography was
1
carried out with Merck silica gel 60F254 plates. All products were characterized by MS, H NMR
and 13C NMR with which compared to the previously reported data. NMR spectra were recorded
at room temperature on a Mercury-Plus 300 or a Bruker AVANCE 400 instrument with TMS as an
internal reference. ESI-MS and EI-MIS were performed on a LCMS-2010A and a Thermo
EI-mass spectrometer respectively. GC/MS was run on a Finnigan Voyager with an electron
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impact (70 eV) mass selective detector and an innowax 30 m × 0.25 mm × 0.25 μm capillary
apolar column. The conditions used for running GC-MS include: 1) initial temperature: 50 ℃; 2)
initial time: 3 min; 3) temperature ramping speed: 20 ℃/min; 4) final temperature: 250 ℃ and
final time: 10 min.
2.2 General procedure for the synthesis of 2a-2t
A 10 mL of vessel was charged with CuO (8 mg, 0.1 mmol), DTPA (78 mg, 0.2 mmol ), aryl
halide (1 mmol), commercial 25- 28% aqueous ammonia (1 mL), KOH (2.0 mmol), H2O (1.0 mL)
and a magnetic stirring bar. The vessel was sealed with a septum and placed into an oil bath which
was preheated to 100 ℃. The reaction mixture was held at this temperature for given time. After
cooling to room temperature, the reaction mixture was extracted with ethyl acetate (3 × 25 mL).
The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel
(eluting with petroleum ether/ethyl acetate) to afford the desired products.
2.3 Procedure for the re-use of the catalysis system in amination of 4-iodoanisole with aqueous
ammonia
A 10 mL of vessel was charged with CuO (8 mg, 0.1 mmol), DTPA (78 mg, 0.2 mmol ),
4-Iodoanisole (1 mmol), commercial 25-28% aqueous ammonia (1 mL), KOH (2.0 mmol), H2O
(1.0 mL) and a magnetic stirring bar. The vessel was sealed with a septum and placed into an oil
bath which was preheated to 100 ℃. The reaction mixture was held at this temperature for 6
hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate in
the vessel to remove 4-methoxyaniline and then bubbled with compressed air for 20 min to
remove residual ammonia and EtOAc thoroughly. Then, 4-iodoanisole (1.0 mmol), aqueous
ammonia (1 mL) and KOH (2.0 mmol) were added into the same vessel. The procedure was
repeated for four times.
3. Results and discussion
Ethylenediaminetetraacetic acid (EDTA) is a water-soluble polyamino carboxylic acid. EDTA
and its salts have been widely used as chelating ligands to form water-soluble complexes with
various metal ions including Cu (II). We first explored the possibility of CuO/EDTA as a catalyst
system for the coupling reaction of 4-bromoanisole with aqueous ammonia in water. As shown in
Table 1 (entry 1), this model reaction generated the target product in 100% conversion and 80%
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normalized yield based on the GC results. Hence, other salts of EDTA have been chosen as
ligands for the same model reaction. It showed that EDTA-2Na and EDTA-2K gave the similar
conversions and yields as EDTA, which was higher than EDTA-3K and EDTA-4Na (entries 2-5,
Table 1). It is noted that the yields of the target product for these model reactions were noticeably
lower than the corresponding conversions, which is mainly due to the side reaction of the
hydrolysis of 4-bromoanisole in alkaline aqueous solution (verified by GC-MS analysis). In
contrast, DTPA, another polyamino carboxylic acid, showed higher conversion and final yield
compared to EDTA and its salts (entry 6, Table 1). In addition, the control reactions without
ligand (entry 7, Table 1) or copper catalyst (entry 8 Table 1) only yielded trace amount of product
after 12 h reaction at 100 ℃, which suggested that both the copper and ligands were critical for an
efficient coupling reaction. There seemed no significant difference between the yields obtained
with copper (II) and copper (I) under the same reaction conditions (entries 9, 10, Table 1).
However, copper powder appeared less effective compared to copper (II) and (I) (entry 11, Table
1). Among all the copper compounds evaluated, CuO provides the best catalytic effect when
coupled with DEPA (entry 6, Table 1).
To further optimize the reaction conditions, bases, reaction time and temperature, phase-transfer
catalysts, as well as different ratios of substrates, catalysts and ligands were screened using the
same model reaction. The results in entries 6, and 12-14 (Table 1) indicated that KOH was the best
base among the several bases screened. It was also found that 10 mol% of CuO and 20 mol% of
DTPA formed the optimal catalyst system. Either decrease or increase in the ligand loading
(without changing the amount of CuO used) led to the lower yields (entries 15-18, Table 1). In
particular, when the ligand ratio was 40 mol%, the GC yield was drastically decreased to 5%.
However, if the loading of the catalyst and ligand were increased simultaneously to the same ratio,
the yield of the product did not show significant change (entries 19, 20, Table 1). The similar trend
was observed for the reactions catalyzed by the CuO/EDTA, whereas EDTA-2Na showed less
sensitivity to the increasing of the ligand load (entries 21, 22, Table 1). The experiments showed
that the pH value of reaction system could be changed by the quantity of added ligand, while the
outcome of the reaction was pH dependent. A more screening of experimental conditions showed
that the yield of the target product did not change significantly when n-Bu4NBr or PEG-400 was
used as phase transfer catalysts (entries 23, 24, Table 1). When the volume of NH3·H2O was
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decreased from 1 mL to 0.75 mL, the yield decreased slightly (entry 25, Table 1). Further
investigation of reaction time and temperature revealed that the reactions performed at 90 ℃ or
for shorter time provided slightly lower conversions and yields (entries 26, 27, Table 1).
Table1. Optimization of the reaction conditions for the amination of 4-bromoanisole with
aqueous ammonia.a
Entry Copper[mol%] Ligand[mol%]
Base[mol%]
KOH [200]
Conv./Yield(%)b
100/80
98/81
1
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
none
EDTA [20]
2
EDTA-2Na [20] KOH [200]
3
EDTA-2K [20]
EDTA-3K [20]
KOH [200]
KOH [200]
94/81
4
86/71
5
EDTA-4Na [20] KOH [200]
40/33
6
DTPA [20]
none
KOH [200]
KOH [200]
KOH [200]
KOH [200]
KOH [200]
KOH [200]
K2CO3 [200]
K3PO4 [200]
100/87
trace
7
8
DTPA [20]
none
9
Cu(NO3)2 [10] DTPA [20]
100/82
100/78
95/67
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Cu2O [10]
Cu [10]
DTPA [20]
DTPA [20]
DTPA [20]
DTPA [20]
DTPA [20]
DTPA [10]
DTPA [15]
DTPA [30]
DTPA [40]
DTPA [30]
DTPA [40]
EDTA [40]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [15]
CuO [20]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
CuO [10]
55/44
43/38
Cs2CO3 [200] 89/76
KOH [200]
KOH [200]
KOH [200]
KOH [200]
KOH [200]
KOH [200]
KOH [200]
30/27
99/75
79/61
10/5
100/87
89/73
62/47
100/77
100/86c
10087d
99/82e
98/82f
89/76g
EDTA-2Na [40] KOH [200]
DTPA [20]
DTPA [20]
DTPA [20]
DTPA [20]
DTPA [20]
KOH [200]
KOH [200]
KOH [200]
KOH [200]
KOH [200]
a Reaction conditions: 4-bromoanisole (1.0 mmol), 25–28% aqueous NH3·H2O (1 mL), Copper, ligand, base, H2O
(1 mL), 100 °C, 12 h.
b Calculated by GC-MS according to the area of peaks.
c Add PEG-400 (0.2g).
d Add TBAB (20 mol%).
e 25–28% aqueous NH3·H2O (0.75 mL).
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f 90 °C.
g 10 h.
After optimizing all reaction parameters, the direct amination of various aryl halides, including
alkyl, alkoxy, halogen, ketone, nitro, carboxyl, ester, cyano and amino groups as substituent, with
aqueous ammonia in water was explored to further investigate the efficiency of the
above-mentioned catalyst system. The results were summarized in Table 2. Most of the activated
and deactivated aryl iodides provided the desired products in high yields, except for
1-iodo-4-nitrobenzene, which generated significant amount of undesired byproduct, nitrobenzene,
due to the high reactivity of iodo group. (entry 13, Table 2) Moreover, the para- or
meta-substituted aryl bromides bearing electron-donating or electron-withdrawing groups
provided high yields of the corresponding primary amines. Furthermore, reaction of aryl bromides
bearing electron-donating ortho-substituent exhibited lower reactivity with aqueous ammonia and
afforded the corresponding product only in medium yield even with the prolonged reaction time to
36 h (entry 16, Table 2). However, reactions of aryl bromides bearing electron-withdrawing
ortho-substituent, such as carboxyl and nitro group, show much higher yields (entries 18, 19,
Table 2). The catalyst system still displayed high activity to the amination of hetero aryl bromides
with aqueous ammonia (entries 25, 26, Table 2).
It is noteworthy that the aryl bromides containing easily hydrolyzed ester and cyano groups as
substituent provided good yields of the corresponding hydrolytic products (entries 14, 15, Table 2).
In addition, attempts to perform the amination of 4-chloroanisole with aqueous ammonia under the
experimental conditions failed; only trace amount of the corresponding coupling product was
detected (entry 6, Table 2). Moreover, we investigated the amination of 4-bromophenol and
4-bromobenzaldehyde with aqueous ammonia to examine the tolerance of the functional groups
towards alcohols and aldehydes. Unfortunately, the reactions did not provide practical yields of
desired compounds, because many side reactions, including debromination, hydrolysis, C-O
coupling reaction (for alcohols) and cannizzaro-type reaction (for aldehydes), readily took place in
alkaline aqueous solutions.
Table 2. CuO/ DTPA -catalyzed amination of aryl halides. a
Entry Aryl halide
1
Product
Yield[%]b
79
1a
2a
2
3
4
5
81
1b
2b
2b
80c
80
1c
1d
2c
80c
1e
2c
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6
7
8
9
trace
63
1f
2c
1g
2d
61
1h
2e
72
1i
2f
10
11
73
1j
2g
67 c
1k
2g
12
13
51
1l
2h
46 c
1m
1n
2h
14
15
59
80
2i
1o
2j
25
16
17
18
19
20
34d
42e
1p
2k
2k
39
74d
66e
1q
71
87
85
1r
2l
1s
2m
1t
2n
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21
73
1u
2o
22
23
73
1v
2p
79c
1w
2q
24
74c
1x
2r
25
26
81
72
1y
2s
2t
1z
a
Reaction conditions: aryl halide (1 mmol), commercial 25-28% aqueous NH3·H2O (1 mL.), CuO (0.1 mmol),
DTPA (0.2 mmol), KOH (2 mmol), H2O (1 mL), 100 ℃, 12 h.
b Isolated yield.
c 6 h.
d 24 h.
e 36 h.
Because the CuO/ligands catalyst system is water soluble and can be easily separated from
aniline products via simple organic/aqueous extraction, we investigated the recycling of this
homogeneous catalyst system and solvent for the amination of 4-iodoanisole with aqueous
ammonia. At the end of the coupling reaction, the reaction solution was extracted with ethyl
acetate to remove the product. Then, in the same vessel, the reactants, 4-iodoanisole and aqueous
ammonia as well as the base, were added for continuous coupling reaction. We were able to run
four consecutive aminations with only slightly decrease of isolated yields (Fig. 1), suggesting the
possible re-use of the current catalyst system.
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100
80
60
40
20
0
0
1
2
3
4
Run
a
Reaction conditions for run 1: 4-iodoanisole (1 mmol), commercial 28% aqueous NH3·H2O (1 mL.), CuO (0.1
mmol), DTPA (0.2 mmol), KOH (2 mmol), H2O (1 mL), 100 ℃, 6 h.
b Reaction conditions for run 2-5: Add 4-iodoanisole (1.0 mmol), aqueous NH3·H2O (1 mL), KOH (2.0 mmol).
Fig. 1. Reuse of the catalyst system and solvent
4. Conclusion
In summary, a simple, recyclable and environmentally friendly homogeneous CuO/DTPA
catalyst system has been established for the direct amination of aryl halides with aqueous
ammonia in water without any surfactants being used. High yields were obtained with a wide
range of aryl iodides and aryl bromides as substrates without the protection of an inert atmosphere.
Furthermore, the reaction system, including catalyst, ligand and solvent, can be simply reused for
four times with only slight loss of its activity.
Acknowledgments
We thank the National Natural Science Foundation of China (Grant No. 21272282, 20802095
and 20872182) and the Fundamental Research Funds for the Central Universities for their
financial support.
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Highlights




Aqueous ammonia was used for the synthesis of primary aryl amines in water.
Homogeneous CuO/ DTPA catalyst system showed superior catalytic activity.
Amination of aryl halides in water could be carried out without any surfactant.
The reaction system could be reused for 4 times with slight loss of its activity.
11