Highly efficient and scale-up synthesis of propargylamines catalyzed by graphene oxide-supported CuCl2 catalyst under microwave condition

Article abstract of DOI:10.1016/j.catcom.2014.05.030

An efficient, green and practical approach was developed to synthesize propargylamines using recyclable GO-CuCl₂ via a one-pot multicomponent aldehyde-alkyne-amine (A³) coupling reaction. The propargylamines are readily obtained in g

Full text of DOI:10.1016/j.catcom.2014.05.030

Highly efficient and scale-up synthesis of propargylamines catalyzed by
graphene oxide-supported CuCl2 catalyst under microwave condition
Xingquan Xiong, Huixin Chen, Rongjun Zhu
PII:
DOI:
Reference:
S1566-7367(14)00211-8
doi: 10.1016/j.catcom.2014.05.030
CATCOM 3924
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
30 March 2014
30 May 2014
31 May 2014
Please cite this article as: Xingquan Xiong, Huixin Chen, Rongjun Zhu, Highly effi-
cient and scale-up synthesis of propargylamines catalyzed by graphene oxide-supported
CuCl2 catalyst under microwave condition, Catalysis Communications (2014), doi:
10.1016/j.catcom.2014.05.030
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ACCEPTED MANUSCRIPT
Highly efficient and scale-up synthesis of propargylamines
catalyzed by graphene oxide-supported CuCl2 catalyst under
microwave condition
Xingquan Xiong*, Huixin Chen, Rongjun Zhu
College of Materials Science & Engineering, University of Huaqiao, Xiamen 361021,
China.
E-mail address: xxqluli@hqu.edu.cn
Abstract:
An efficient, green and practical approach was developed to synthesize
propargylamines using recyclable GO-CuCl2 via a one-pot multicomponent
aldehyde-alkyne-amine (A3) coupling reaction. The propargylamines are readily
obtained in good to excellent yields (85-96%) and on multi-gram scale (88%, 150
mmol) under microwave irradiation. GO-CuCl2 could be easily recovered through
filtration and reused at least five recycles with no significant decreases in the yields.
Keywords: Propargylamines, A3-coupling, GO-CuCl2, Green chemistry
1. Introduction
Propargylamines not only are important structural elements in natural products and
pharmaceutical preparations, but also are versatile synthetic intermediates, which
have attracted increasing academic attention [1]. Because of the potent usefulness of
propargylamines, several synthetic methods have been developed to synthesize them.
Traditionally, the reaction of lithium acetylides or Grignard reagents with imines or
their derivatives is applied for the synthesis of propargylamines [2]. However, the use

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of stoichiometric amounts of organometallic reagents, and strictly controlled reaction
conditions are required. The protecting groups are also needed because of the
instability of aldehydes. Thus, the development of the environmentally benign and
cost-efficient protocols has been demanded. Recently, the synthesis of
propargylamines has been successfully carried out using an atom-economic approach
of one-pot three-component A3-coupling [3], where water is merely theoretical
by-products.
Firstly, homogeneous catalysts such as Zn salts [4], Cu salts [5], Fe salts [6], Ag
salts [7], Au salts [8], and etc. are applied for the reaction. Unfortunately, the
homogenous catalysts suffer from drawbacks such as the loss of the precious or
hazardous catalysts at the end of the reaction. In order to overcome these drawbacks,
heterogeneous catalysts have been widely investigated for A3-coupling reaction due to
their thermal stability, reusability and high catalytic activities.
Subsequently, a number of methods have been developed to immobilize metal salts
on various solid supports, such as zeolite [9], organosilica [10], polymers [11,12] and
so on [13-18]. However, most of them have certain drawbacks, such as long reaction
time, complex catalyst preparation processes and involvement of expensive reagents.
So, most of the above mentioned approaches may cause economic and environmental
concerns when large-scale synthesis of propargylamines is considered.
Different from the above solid supports, graphene oxide (GO) has been
demonstrated as a promising material for heterogeneous catalysts because of high
chemically stability and good accessibility. Furthermore, the abundance of functional

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groups on its basal planes and edges of GO is also a key factor for the further
chemical mdification [19].
Microwave (MW) technology has gained widespread popularity in organic
synthesis, mainly due to its obvious reductions in reaction time and significant
enhancements in conversions [20, 21]. It was shown that MW irradiation was very
necessary for speeding up synthesis of propargylamines [22-28]. As a part of our
continuing interest in the further improvement the practicability and efficiency of MW
technology [29-31], herein we report an efficient and green strategy for scale-up
synthesis of propargylamines, which catalyzed by GO-CuCl2 under MW irradiation.
GO-CuCl2 could be separated conveniently and reused at least five times without a
significant drop in the yields. The propargylamines can be prepared in 88% yield and
on multi-gram scale (150.0 mmol).
[Insert Scheme 1]
2. Experimental section
2.1 Preparation of GO-CuCl2
GO (0.25 g) was dispersed in toluene (40.0 mL) by sonication for an hour to obtain
a light brown dispersion and 3-aminopropyltriethoxysilane (APTS) (1.32 g) was
o
added when the solution was heated to 90 C. The mixture was stirred overnight at
this temperature. Finally, the GO-APTS was filtered, washed with ethanol, and dried
under vacuum at 40 oC. GO–APTS (0.2 g) was dispersed in N, N-dimethylformamide
(DMF) (40.0 mL) by sonication for an hour and then CuCl2 (0.05 g) was added. It was
stirred at room temperature for 6 hours. The GO–CuCl2 catalyst was separated

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through filtration, washed with deionized water and ethanol followed by drying under
vacuum at 40 oC overnight for further use.
2.2 A3-Coupling Reaction
GO-CuCl2 was added to a reaction mixture of aldehyde, alkyne and amine. The
combined mixture was refluxed under microwave irradiation. After complete
conversion of the aldehyde, let the mixture cool to room temperature and the mixture
was filtered, extracted by EtOAc and dried. After the evaporation of the solvent, the
crude product was obtained. Purification was performed by flash column
chromatography to afford propargylamines in good to excellent yields.
3. Results and discussion
3.1 Catalyst characterization
FTIR spectra of GO, GO-APTS and GO-CuCl2 are shown in Fig. S1. For GO, the
peaks at 3417 and 1722 cm-1 were attributed to the stretching mode of OH and the
asymmetric stretching mode of C=O, respectively. For GO-APTS, new peaks at 2923
and 2854 cm-1 were assigned to the asymmetric and symmetric stretching modes of
C−H in APTS. The sharp peak at 1384 cm-1 was characteristic stretching band of the
C−O−C [32]. The peaks at 1118 and 1037 cm-1 were characteristic bands of the
Si−O−Si, indicating that the surface of GO was successfully modified with APTS.
After complexation with CuCl2, the peaks at 1643, 1118 and 1037 cm-1 were shifted to
1631, 1116 and 1041 cm-1, respectively. This is probably caused by the coordination
effect of CuCl2 with the monodentate and bidentate ligands APTS.

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The copper contents of GO-CuCl2 and the reused catalyst after five recycling were
found to be 11.28 and 9.25 wt% by AAS, respectively (Table 1). It can be further
confirmed that the copper contents of catalyst is not evidently decrease by the
following tests.
[Insert Table 1]
The typical TEM images of GO and GO-CuCl2 were shown in Fig. 1A and 1B,
respectively. As can be seen from Fig. 1A, TEM image of the GO exhibited the
ordered stacking of multilayer. From Fig. 1B, the TEM image of GO-CuCl2
confirmed that the silanization and the complexation between CuCl2 and the amino
groups of APTS caused no significant damage to the GO sheet structure. From Fig.
1B, we can also see that CuCl2 species are well dispersed on the surface of amine
modified GO. The results indicated that amine groups on the surface of GO played an
important role to improve the dispersibility of CuCl2 and the nano-sized
organic-inorganic hybrid material was obtained.
The typical SEM images of GO-CuCl2 and the recycled catalyst after 5 consecutive
trials were shown in Fig. S2. The surface morphology of the recycled catalyst did not
show any significant change even after 5 reaction cycles. Energy dispersive X-ray
spectroscopy (EDS) mapping images showed that CuCl2 were dispersed uniformly
onto GO sheet by the complexation (Fig. 2a). However, the copper content of
GO-CuCl2 after five recycling is a slight decrease compared with the fresh catalyst
(Fig. 2b), which showed GO-CuCl2 has good stability during the A3-coupling
reaction.

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[Insert Figure 1]
[Insert Figure 2]
XRD patterns are showed in Fig. S3. GO shows a sharp peak at 10.9°,
corresponding to the (001) reflection. In GO-APTS, the intensity of the peak at 10.9°
significantly decreased, and an obvious peak at 2θ=21.4° appeared, indicating that
APTS was conjugated onto the surface of GO. GO-CuCl2 showed the characteristic
reflections for CuCl2 at 2θ=14.7°, 21.4° and 33.2° corresponding to the planes (110),
(020) and (201) of cubic CuCl2 crystal, respectively. The results showed GO–CuCl2
had been prepared successfully.
TGA curves are showed in Fig. 3. GO was thermally unstable and the whole weight
loss of GO is ca. 63% at 210°C, which is presumably due to the removal of adsorbed
water and pyrolysis of the thermally unstable oxygen-containing groups. For
GO-CuCl2, a better thermal stability than GO, a much slower and lower mass loss was
observed, which might be assigned to the decreased decomposition of
oxygen-containing groups.
[Insert Figure 3]
3.2 Effect of the copper source
In order to investigate the optimized conditions, the catalytic activities of
homogeneous and heterogeneous catalysts were examined in a model reaction using
benzaldehyde, phenylacetylene and morpholine as starting materials under
solvent-free conditions at 90°C. The results are summarized in Table 2.

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When the reaction were catalyzed by CuCl2 and CuBr under MW and conventional
heating, 4-(1,3-diphenylprop-2-ynyl)morpholine could be obtained in 95, 83 and 87%
yield, respectively. However, these catalysts cannot be reused. To ensure the
reusability of catalyst, C-CuCl2, SiO2-CuCl2, and GO-FeCl3 were employed as
heterogeneous catalysts. Unfortunately, these heterogeneous catalytic systems
resulted in poor to moderate yields yields (40-70%). To our delight, after screening
experiments with GO-CuCl2, the product could be obtained in excellent yields of 95
and 96% under MW and conventional heating, respectively. Comparing with the
traditional heating (8 hours), the use of MW could dramatically reduce reaction time
(20 min).
The copper metal contamination in the final products is a major concern because of
the use of homogeneous copper salts catalytic system. These drawbacks counteract
their applications in the fields of biomedicine and pharmaceuticals. So the copper
content in the obtained product was detected by AAS. In homogeneous catalytic
system, such as CuCl2, the copper content in the product was 3.26 (wt%), which was
far more than 0.006 (wt%) in GO-CuCl2 catalytic system. Clearly, the copper content
of the obtained product in the heterogeneous reaction is ignorable.
[Insert Table 2]
3.3 Synthesis of propargylamines
To extend the scope of the reaction, various aldehydes, amines and alkynes were
tested (Table 3). All the A3-coupling reactions proceeded smoothly to give the
propargylamines in high yields, which clearly reveal the efficiency and generality of

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the developed protocol. The reactivity of 4-methoxybenzaldehyde was found to be
less reactive than that of benzaldehyde or 4-chlorobenzaldehyde. It was lower yield
when 4-methoxybenzaldehyde was treated with corresponding terminal alkynes and
secondary amines. Unfortunately, primary aromatic and arylalkyl amines, such as
n-Butylamine, benzylamine and aniline, did not yield the coupled products even after
long reaction times.
Various alkynes with electron withdrawing and donating groups were also studied.
It was observed that there was no significant difference in reactivity for the examined
reactants with varied electronic properties. Both electron-poor and electron-rich
alkynes as reactants generated good to excellent yields (Entries 8–11, 85-94%).
It is worth noting that when compared with other similar heterogeneous catalysts
(such as 4Å molecular sieve-supported copper(II) catalyst [33]), GO–CuCl2 showed
higher catalytic activity (20 min, 85-98%) under MW irradiation. Although under
traditional heating conditions, the reaction also could proceed smoothly to completion
in 96% yield within 8 h. The semi-heterogeneous and good accessible properties of
the GO-CuCl2 catalyst might cause the extremely high catalytic activity.
[Insert Table 3]
3.4 Reuse test of GO–CuCl2
In order to enhance the efficiency and reduce waste, the reuse of GO-CuCl2 in the
model reaction was investigated. GO-CuCl2 could be easily recovered through by
filtration and washed, then new substrates were added for the next cycle. Fig. 4
showed a summary of the obtained results, which indicated no significant decreases in

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yields after 5 cycles (96-88%), suggesting that CuCl2 leaching is not significant for
GO-CuCl2.
[Insert Figure 4]
3.5 Scale-up experiment
To further investigate the feasibility of applying this method in a preparative scale,
the scale-up experiment was carried out in the presence of formaldehyde,
phenylacetylene and diethylamine under the optimum conditions. The detailed results
were summarized in the Table 4.
We conducted a series of amplification experiments and increased the scale of the
reaction to 3.0, 30.0, 60.0 and 150.0 mmol, keeping the reaction stoichiometry
unchanged. These reactions were found to proceed smoothly and the product was
obtained in 88-96% yields. When the scale of the reaction was increased to 150.0
mmol, N,N-diethyl-3-phenylprop-2-yn-1-amine could be obtained in 88% yield.
Furthermore, when the scale was 30.0 mmol, GO-CuCl2 could be reused at least five
times and still maintained a moderate yield.
[Insert Table 4]
3.6 Tentative reaction mechanism
On the basis of the obtained results, a proposed reaction mechanism for the A3
coupling reaction catalyzed by GO-CuCl2 under
was
illustrated in Scheme 2. At first, Cu(II) catalyzed A3 coupling reaction could be
promoted under microwave-assisted conditions by activation of the C-H bond of

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terminal alkyne to afford the desired copper–alkylidine complex on the surface of GO
support. Similarly, the formation of iminium ion could also be promoted under the
same conditions. Subsequently, the copper–alkylidine complex added to iminium ion
to give the corresponding propargylamine.
[Insert Scheme 2]
4. Conclusions
A series of propargylamines were synthesized using GO-CuCl2 as catalyst via
multicomponent A3-coupling reaction. The reactions were carried out at a relatively
lower temperature, in shorter reaction time under solvent-free condition, which gave
good to excellent yields. The results showed that GO-CuCl2 not only has the very high
catalytic activity but also could be recovered and reused 5 recycles without significant
loss of catalytic activity. Meanwhile the further investigation of the scale-up reaction
has been done successfully, which is performed in 150.0 mmol scale and achieved
88% yield.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of
China (21004024), the Natural Science Foundation of Fujian province (2011J01046),
the Program for New Century Excellent Talents in University of Fujian province
(2012FJ-NCET-ZR03) and the Promotion Program for Young and Middle-aged
Teacher in Science and Technology Research of Huaqiao University (ZQN-YX103).

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Captions
Scheme 1. Multicomponent synthesis of propargylamines catalyzed by GO–CuCl2.
Scheme 2. Tentative mechanism for the synthesis of propargylamine catalyzed by
GO-CuCl2 under MW irradiation.
Figure 1. TEM images of GO (a) and GO-CuCl2 (b)
Figure 2. SEM/EDX images of GO-CuCl2 (a) and GO-CuCl2 after 5 recycling (b)
Figure 3. TGA curves of graphite, GO and GO-CuCl2.
Figure 4. Recyclability results of GO-CuCl2.
Table 1. FTIR and microanalysis results.
Table 2. Effect of the catalysts on the A3-coupling.a
Table 3. A3-coupling reaction catalyzed by GO-CuCl2.a
Table 4. Scale-up synthesis of N,N-diethyl-3-phenylprop-2-yn-1-amine.

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Scheme 1. Multicomponent synthesis of propargylamines catalyzed by GO–CuCl2.
R4
R2
R5
GO-CuCl2
O
N
H
free of solvent
One-pot, MW
R1
N
+
+
R4
R5
R2
R3
R3
R1
HO
HO
O
O
O
O
O
O
OH
OH
EtO
Si OEt
Si
(II)
Cu
NH2
NH2
GO-CuCl2

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Scheme 2. Tentative mechanism for the synthesis of propargylamine catalyzed by
GO-CuCl2 under MW irradiation.
R3
R2
R4
H
R1
N
GO-CuCl2
OH-
Microwave
Microwave
R1
O
H
GO-CuCl2
H2O
N
R3
R2
R4
R2
H
R3
R4
H
R1

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Figure 1. TEM images of GO (a) and GO-CuCl2 (b).

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Figure 2. SEM/EDX images of GO-CuCl2 (a) and GO-CuCl2 after 5 recycling (b).
a
b

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Figure 3. TGA curves of graphite, GO and GO-CuCl2.
graphite
GO-CuCl
100
80
60
40
20
0
2
GO
200
400
600
800
Temperature (oC)

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Figure 4. Recyclability results of GO-CuCl2.

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Table 1. FTIR and microanalysis results.
FTIR (KBr, cm–1)
–
AAS results (wt%)
Sample
GO
νC=O
1722
–
νC=C νSi−O−Si νSi−O−C
Cua
–
Cub
–
1634
1643
1631
–
–
GO-APTS
GO-CuCl2
1118
1116
1037
1041
–
–
–
11.28
9.25
[a] AAS result of fresh catalyst. [b] AAS result of GO–CuCl2 after five consecutive trials.

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Table 2. Effect of the catalyst on the A3-coupling.a
Entry
catalyst
CuCl2
Yield (%) b
83/95c
87
1
2
3
4
5
6
CuBr
C-CuCl2
60
SiO2-CuCl2
GO-FeCl3
GO-CuCl2
70
40
95/96c
[a] Benzaldehyde (3.0 mmol), alkyne (3.6 mmol), amine (3.6 mmol), catalyst (10 mg).
[b] Isolated yields under microwave heating condition, 400W, 90 °C, 20 min.
[c] Isolated yields by using conventional heating, 8 h.

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Table 3. A3-coupling reaction catalyzed by GO-CuCl2.a
R4
R5
O
N
H
GO-CuCl2
R1
N
+
+
R4
R5
O
R2
R3
400 W, 90 oC
2
R3
R
R1
H
N
Yield
(%)b
R1
Entry
R4
R5
R2
R3
CHO
O
NH
1
2
3
4
5
6
96
98
92
85
88
96
O
O
O
O
O
NH
NH
NH
NH
CHO
Cl
CHO
O
CHO
HCHO
HCHO
N
H
HN
O
7
HCHO
97
H3CO
H3CO
O
O
NH
NH
8
HCHO
HCHO
HCHO
HCHO
HCHO
HCHO
HCHO
94
92
93
85
0
N
H
9
O
O
10
11
12
13
14
O
O
N
H
O
0
0
[a] Benzaldehyde (3.0 mmol), alkyne (3.6 mmol), amine (3.6 mmol), GO-CuCl2 (10 mg), 20 min.
[b] Isolated yields.

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Table 4. Scale-up synthesis of N,N-diethyl-3-phenylprop-2-yn-1-amine.
Entry
1
Scale (mmol)
Yield (%)a
3
30
60
150
30
30
30
30
96
91
90
88
89
88
83
70
2
3
4
5b
6c
7d
8e
[a] Isolated yields; [b] Catalyst recycled from entry 2 and used for second run; [c] Third run; [d]
Fourth run; [e] Fifth run.

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Graphical abstract
R4
R2
R5
GO-CuCl2
free of solvent
One-pot, MW
O
N
H
N
R1
+
+
R4
R5
R2
R3
R3
R1
HO
HO
(85-98%)
O
O
O
O
O
O
OH
OH
EtO
Si OEt
Si
(II)
Cu
NH2
NH2
GO-CuCl2

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Highlights
 GO–CuCl2 was prepared for on GO support.
Propargylamines are readily obtained in good to excellent yields and on multi-gram
scale.
GO-CuCl2 could be easily recovered and reused at least five recycles.