Copper(II) carboxymethylcellulose (CMC-CuII) as an efficient catalyst for aldehyde-alkyne-amine coupling under solvent-free conditions

Article abstract of DOI:10.1039/c6ra18742k

A novel and eco-friendly three-component reaction of aldehydes, amines, and alkynes (A3 coupling) catalyzed by a recoverable copper(ii) carboxymethylcellulose (CMC-Cu^II) catalyst has been developed, producing a diverse range of propargylamines under solvent-free conditions in good yields. The CMC-Cu^II catalyzed reaction is especially effective for reactions involving aromatic and aliphatic aldehydes. High catalytic activity was obtained in the presence of 5 mol% CMC-Cu^II without any other co-catalyst, additives, or bases under aerobic conditions. Moreover, the catalyst can be easily recovered and reused for at least four cycles without significant decrease in its catalytic activity.

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Copper(II) carboxymethylcellulose (CMC-CuII) as an efficient
catalyst for Aldehyde-Alkyne-Amine coupling under solvent-free
conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaoping Liu, Bijin Lin, Zhuan Zhang, Hao Lei and Yiqun Li*
DOI: 10.1039/x0xx00000x
A novel and eco-friendly three-component reactions of aldehydes, amines, and alkynes (A3 coupling) catalyzed by
recoverable copper(II) carboxymethylcellulose (CMC-CuII) catalyst has been developed, producing a diverse range of
propargylamines under solvent-free condition in good yields. The CMC-CuII catalyzed reaction is especially effective for
reactions involving aromatic and aliphatic aldehydes. High catalytic activity was obtained in the presence of 5 mol% CMC-
CuII without any other co-catalyst, additives, or bases under aerobic conditions. Moreover, the catalyst can be easily
recovered and reused for at least four cycles without significant decreasing in its catalytic activity.
www.rsc.org/
species. A variety of transition metal catalysts have been reported
to promote this three component reaction. These include transition
metal salts or complexes such as Au,5 Ir,6 Ag,7 Fe,8 Ni,9 Zn,10 Co,11
Introduction
Muticomponent reactions (MCRs) combine at least three starting
components into the product consisting of the largest number of
atoms of each starting substrates in a single one-pot process.1 The
transition metal catalyzed MCRs are powerful synthetic tools in the
synthesis of diverse complex compounds from simple substrates.1b
Among the numerous transition-metal catalyzed MCRs, the three
component reaction (3CR) of aldehyde, amine, and alkyne
(commonly called A3 coupling)2 is one of the well-known examples
as it produces valuable N-containing heteroatom propargylamine
product. Propargylamines are not only important structural
moieties present in natural products and potential pharmaceutical
molecules, but also versatile synthetic blocks in various organic
transformations.3 Due to their significance, great effort has been
made to the synthesis of these compounds. Conventional synthetic
protocols for propargylamines include nucleophilic addition of
lithium acetylides or Grignard reagents to imines or their
derivatives.4 However, in most case, these procedures require the
employment of stoichiometric amounts of organometallic reagents
under strictly controlled moisture- and air-free conditions. An
efficient alternative atom-economical approach is to perform this
type of reactions by a catalytic coupling of aldehyde, alkyne, and
amine via C―H acꢀvaꢀon, in which water is the only by-product.
The importance of this reaction inspires many chemists to seek new
highly active and stable catalysts, mostly based on transition metal
Cu,12 and Cu/Ni,13 Cu/Ru14 bimetallic system under homogeneous
reaction conditions. Despite the efficiency of these catalysts,
homogeneous catalysts suffer from the drawbacks of recovery and
catalytic reuse which severely obstruct their wide use in academic
and industrial areas. In order to achieve recyclability of the
catalysts, heterogeneous catalysts have received much more
attentions recently. Compared to the homogeneous catalysts, the
heterogeneous supported catalysts have remarkable characteristics
such as easy separation and regeneration, and good recyclability
and reusability. Proceed along this line, several heterogeneous
catalysts such as supported copper catalysts (Cu-MCM-41, Cu-MS,
Cu-HAP, CuI/A-21),15 supported gold catalysts (LDH-AuCl4, Au/CeO2,
Au/IRMOF-3) ,16 supported silver(Ag-G, Ag-K10)17 were successfully
employed to catalyze A3-coupling reactions. However, these
materials, such as inorganic oxides, polymers, and metal-organic
frameworks (MOFs), have at least one drawback such as lacking of
active catalytic sites, fragile, non-biodegradable, and are unfriendly
to the environment, or their preparation and regeneration is quite
tedious.
Among the reported catalysts, since copper catalysts are cheap,
available, and highly reactive, a lot of copper salts and its complexes
as a source of homogeneous or heterogeneous catalyst were
successfully employed to catalyze A3-coupling reactions. Recently,
several copper heterogeneous catalytic systems were successfully
developed to catalyze A3-coupling reactions.15 However, most of
these copper heterogeneous catalysts were not easily available,
used in toxic solvent or required harsh reaction conditions. As far as
we observed, reports on copper heterogeneous catalysts mobilized
on biodegradable biopolymer are still very limited and it is desirable
a.Department of Chemistry, Jinan University, Guangzhou 510632, P. R. China. E-
mail: tlyq@jnu.edu.cn
b.Address here.
c. Address here.
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: experimental details and
characterization data. See DOI: 10.1039/x0xx00000x
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to develop highly efficient copper catalysts for A3-coupling
reactions under environmentally friendly condition.
1631.2 and 1427.5 cm−1, implying coordination of −COO− with CuII.
(Figure 1).
Sodium carboxymethylcellulose (CMC−Na) with carboxymethyl
SEM images of CMC-CuII showed that the catalyst was made up
groups (−CH2−COO−Na+) bonded on cellulose backbone is capable of of micro-particles with an average diameter of around 100 µm (Fig.
exchanging with metal cations, which makes it an excellent support
to immobilize metal catalyst via ion exchange reaction. Very
recently, we reported the application of cellulose or
2a). Also, the presence of carbon, oxygen and copper in the CMC-
CuII was confirmed by energy-dispersive X-ray spectroscopy (EDX)
(Fig. 2b) associated with SEM analysis. As a result, it is reasonable to
assume that CMC molecules can serve as an effective matrix to
bond Cu(II) species.
carboxymethylcellulose as a support for stabilization of palladium
nanoparticles and its applications in Suzuki–Miyaura and Heck–
Mizoroki coupling reactions.18 In continuation with our interest on
biopolymer-supported heterogeneous catalysts and
XPS was performed to elucidate the valence state of Cu on the
surface region of the catalyst. As shown in Figure 3, the binding
energies of Cu2p in the fresh (Fig.3a) and recovered CMC-CuII (Fig. 3b)
are measured to be 933.6 eV. These results indicated that the
presence of Cu(II) species in both freshly prepared and recovered
CMC-CuII catalyst.
muliticomponent reactions including A3 couplings, herein, we
report the synthesis, characterization, and application of copper(II)
carboxymethylcellulose (CMC-CuII) as an excellent recyclable
catalyst without any additive or base in A3 coupling reactions under
solvent-free condition in the air. To the best of our knowledge, so
far no application of CMC–CuII catalyst in A3-coupling reaction has
been reported in the literature.
Results and discussion
We first describe the preparation and characterization for
carboxymethylcellulose-supported Cu (II) (CMC-CuII) and available
FT-IR, SEM, EDX, and XPS characterization data to understand the
structure of this catalyst before presenting the catalytic activity of
CMC-CuII for A3 coupling.
a
2913.6
1327.0
599.8
1420.0
Scheme 1 illustrates the preparation procedure to obtain CMC-CuII.
Briefly, CMC-CuII was formed by the metathesis of aqueous copper
salts and CMC-Na solution at room temperature. Under this
condition, blue solid precipitated from the solution, indicating
successful formation of CMC-CuII.
1060.8
3424.9
1600.0
b
2363.6
1427.5
1631.2
617.6
1057.2
1119.1
3342.0
The resulting blue solid catalyst was recovered from the liquid
4000
3500
3000
2500
2000
1500
1000
500
phase by filtration and thoroughly washed with distilled water.
Wavenumber(cm-1)
Figure 1 FT-IR spectra of CMC-Na (a), CMC-CuII(b)
CMC-Na (aq)
(aq)
+ Na2SO4 (aq)
+
CuSO4
CMC-Cu(II)
OH
COO
OH
Cu2+
COO
CO2Na
CO2Na
OH
CO2Na OH
Cu2+
ion exchange
Sodium carboxymethylcellulose
CMC-Na
CO2Na
OH
OH
Copper(II) carboxymethylcellulose
CMC-CuII
OCH2COONa
O
OH
b
a
HO
*
CMC-Na
*
Figure 2 SEM image of the fresh CMC-CuII (a); EDX elemental
O
O
HO
O
OH
analysis of CMC-CuII (b).
OCH2COONa
Scheme 1 the preparation procedure of CMC-CuII catalyst.
The catalyst was finally dried at 60 °C till constant weight. The Cu
content was determined to be 2.146 mmol/g by ICP.
The characteristic absorption peaks at 1600 and 1420 cm−1 in the
FT-IR spetrum of CMC-Na are attributed to asymmetric and
symmetric stretching vibration of carboxylate (−COO−) group,
respectively. In the IR spectrum of CMC-CuII, these peaks shifted to
2 | J. Name., 2012, 00, 1-3
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O
N
O
O
H
+
+
N
H
1a
3a
2a
4a
Entry
Catalyst
(mol%)
Solvent
Temp. (
Yieldb
(%)
Time（
h）
15
℃)
100
100
100
100
100
100
100
80
1
2
FeCl3 (10)
-
55
25
59
79
NPc
9
CuSO4 (10)
-
15
3
Cu(OAc)2 (10)
CuI (10)
-
15
4
-
15
5
-
-
15
6
CMC-Na (10)
CMC-CuII (5)
CMC-CuII (5)
CMC-CuII (5)
CMC-CuII (5)
CMC-CuII (5)
CMC-CuII (5)
CMC-CuII (4)
CMC-CuII (5)
CMC-CuII (10)
CMC-CuII (5)
CMC-CuII (5)
CMC-CuII (5)
-
15
(a) Fresh catalyst
7
H2O
12
37
34
28
56
73
79
73
81
74
65
72
72
8
EtOH
15
9
CH3CN
80
15
10
11
12
13
14
15
16
17
18
PEG-400
100
90
15
Toluene
15
Toluene
100
100
100
100
80
15
-
-
-
-
-
-
15
15
15
15
90
15
100
12
a Reaction conditions: benzaldehyde (1 mmol), morpholine (1.2
mmol), phenylacetylene (1.5 mmol) in the air.
bIsolated yields.
c No product.
(b) Recycled catalyst
Figure 3 XPS spectrum of the fresh catalyst (a) and the recycled
It is also found that the catalyst loading greatly affects the yield of
the coupling products. By increasing the amount of the CMC-CuII
catalyst from 4, 5 to 10 mol%, the yield reached up to 73, 81, and
74% respectively (Table 1, entries 13-15).Thus, 5 mol% of catalyst is
believed to be enough to complete the reaction. As evident from
Table 1, the reaction temperature has a significant effect on the
coupling reaction. It was also seen that decreasing the temperature
from 100 to 80 °C provided lower yields (Table 1, entries 15 and 16).
Thus, the results revealed that the best reaction condition for this
catalytic process includes the usage of1.0 equiv of aldehyde, 1.2
equiv of amine, 1.5 equiv of alkyne, together with 5 mol % of CMC-
CuII under neat conditions at 100 °C in the air (Table 1, entry 14).
catalyst (b).
We used benzaldehyde (1a), morpholine (2a) and phenylacetylene
(3a) as standard substrates to search for the optimal condition for
the A3-coupling. Initially, various simple metal salts such as FeCl3,
CuSO4, Cu(OAc)2, CuI and CMC-CuII were investigated for the
coupling reaction (Table 1). The presence of metal catalyst proved
to be crucial for the A3 coupling. No desired product was detected
when the reaction was carried out in the absence of catalyst (Table
1, entry 5). In the control experiment, CMC-Na could not promote
the reaction effectively (Table 1, entry 6). Among all the catalysts
evaluated, CMC-CuII was found to be most effective in catalyzing
the three component coupling. Next, various solvents were
explored for the coupling reaction and higher yields were observed
when nonpolar solvent was used (Table 1, entries 7-12). In addition,
it is noteworthy that the reaction proceeded far more efficiently
under neat condition (Table 1, entries 13-18).
With the optimized reaction conditions in hand, various aldehydes,
amines, and alkynes were screened to explore the scope of the
three-component coupling reaction.The detailed results were
summarized in Table 2. Aryl aldehydes with both electron-donating
and electron-withdrawing functionalities afforded the
corresponding propargylamines in good to excellent yields. In most
cases, aryl aldehydes with electron-withdrawing groups led to
slightly higher yields compared to those with electron-donating
groups, when morpholine and phenylacetylene were employed
(Table 2, entries 2-10). However, with aryl aldehydes carrying
strong electron-releasing groups (i.e. -N (CH3) or -OH), only trace
amount of desired product was isolated (Table 2, entries 11 and12).
When aliphatic aldehydes reacted with morpholine and
Table 1 Optimisation trials for the A3-coupling reactiona
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phenylacetylene, formaldehyde is more active than others, afforded amines (Table 2, entries 18 and 19) were used. By replacing the
the desired product in 80% yield (Table 2, entry 13).
secondary amine with primary aromatic amine (such as aniline), a
significant decrease in the reaction yield was observed (Table 2,
entries 20-22), owing to the stereoelectronic effects making the
nucleophilic attack of the nitrogen atom of the amine more difficult
in forming the intermediate imine. Once again, aliphatic alkyne
leads to lower yield (Table 2, entry 25). Presumably, the aliphatic
alkyne is not as effective in forming a Cu-alkyne intermediate when
compared to aromatic alkynes.
Different amines also underwent the corresponding three-
component coupling reaction smoothly and generated the products
in good to excellent yields. Moderate to good yields were observed
when cyclic dialkylamines such as morpholine, piperidine, and
pyrrolidine (Table 2, entries 1-17, and 23-26) or secondary aromatic
Table 2 CMC-Cu(II)-catalyzed A3-coupling reaction to synthesis a variety of propargylaminesa
R2
R1
R3
O
N
R2
R3
CMC-CuII
N
H
+
+
R4
R1
H
Solvent-free
100 o
C
R4
2
3
1
4
Entry Aldehydes (1)
Amines (2)
Alkynes (3)
Products (4)
Yieldsb (%)
81
O
O
1
H
N
4a
O
N
2
85
86
Cl
4b
3
4c
4
88
4d
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5
78
85
84
4e
6
7
4f
4g
8
82
80
83
4h
9
4i
10
4j
11
trace
4k
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12
trace
4l
13
14
80
60
4m
4n
15
16
55
80
4o
4p
17
18
79
88
4q
4r
Bn
Bn
N
O
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Bn
19
78
N
O
4s
NH2
20
21
trace
4t
20
4u
22
21
4v
23
85
4w
24
25
82%
4x
43
4y
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26
83
4z
a
Reaction conditions: aldehyde (1.0 mmol), amine (1.2mmol), alkyne (1.5 mmol), CMC-Cu (5 mol%), 100 °C, 15h, under solvent-free in the
air.
b Isolated yields.
R3
R4
N
88
90
60
30
0
Cu2+
CMC
85
84
R1
79
R4
R4
4
3
R2
R3
CMC
Cu2+
R1 CHO
+
N
H
R2
R3
H
H
N+
1
R4
2
Cu2+
3A
CMC
R1
R4
4B
R2
R1
R3
H
N+
2A
Run 4
Run 1
Run 2
Run 3
R2
R1
R3
H
N+
Cu2+
R4
H2O
CMC
4A
Scheme 3 Recycling of catalyst for the reaction of 3-
methoxybenzaldehyde, dibenzylamine and phenylacetylene
For the study of recycling abilities of this CMC-CuIIcatalyst, the
model reaction of 3-methoxybenzaldehyde, dibenzylamine and
phenylacetylene under the optimal reaction condition was
investigated (Scheme 3). Results indicated that this catalyst is
recyclable during at least four consecutive runs with only slight
decreasing in its catalytic activity. In addition, the TON (turnover
number) and TOF (turnover frequency) of this reaction, were
calculated to be 18 and 2.1 h-1, respectively. Furthermore, to
determine the nature of the catalysis, we have also performed the
hot filtration test by using the model reaction under the optimal
reaction condition. The reaction was terminated in 1 h (~32%
conversion) by adding excessively hot ethanol to filter out the solid
catalyst. After removal of ethanol, the reaction was then allowed to
react for another 12 h at 100°C under solvent-free condition. After
this time, no further progress in product yield was observed. The
results revealed that essentially no Cu(II) species was leached out
into the reaction mixture and the reaction has truly been catalyzed
by a heterogeneous system.
Scheme 2 Proposed reaction mechanism for the A3-coupling
Proposed mechanism for the reaction is based on the reported
metal-catalyzed A3- coupling reaction mechanism (Scheme 2). It is
suggested that the A3 coupling proceeds initially by activation of
alkyne by Cu(II) (3A). After deprotonation, the alkyl-Cu intermediate
was coordinated with the iminium ion (2A) generated in situ from
the aldehyde and amine to form the activated complex (4A), which
was further nucleophilic attacked by alkyl-Cu to produce the
corresponding propargylamine (4) and regenerate the Cu(II) catalyst
for further cycling.
For practical applications of heterogeneous catalyst, the reusability
of catalyst is a very important factor.
Experimental
FT-IR spectra were recorded on a Nicolet 6700 spectrometer as KBr
pellets in the range 4000−400 cm−1. 1H NMR (300MHz) and 13C NMR
(75MHz) spectra were obtained with a Bruker Avance instrument
with CDCl3 as solvent and TMS as internal standard. HRMS data
were recorded using AB SCIEX Triple TOF 5600+ detection. The
elemental copper content of polymeric catalysts was determined by
PerkinElmer Optima 2000DV inductively coupled plasma-atomic
emission spectrometry (ICP-AES). X-ray photoelectron spectroscopy
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(XPS) measurements were performed on a KratosAxis UltraDLD X-ray
photoelectron spectrometer with an Al Kα excitation. Scanning
electron microscopy (SEM) and energy-dispersive X-ray (EDX) were
performed with JEM-2100F instrument. All chemicals were
obtained from commercial sources and used as received.
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Preparation of copper(II) carboxymethylcellulose (CMC-
CuII)
The 1 wt % aqueous solution of sodium carboxymethylcellulose was
added dropwise to an aqueous solution containing 10 wt %
.
CuSO4 5H2O with constantly stirring at room temperature. The blue
solid was precipitated immediately and further left equilibrate in
solution for 6 h. The resulting solid was separated from the solution
by suction filtration and washed thoroughly with distilled water,
then dried in vacuum to constant weight to provide the CMC-CuII as
blue powder. The Cu content was determined to be 2.146 mmol/g
by ICP-AES.
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A mixture of aldehyde (1.0mmol), amine (1.2mmol) and
phenylacetylene (1.5mmol) and a catalytic amount of CMC-CuII (5
mol %) was stirred in neat at 100°C in air for 15h. After the
completion of reaction, 30mL EtOAc was added to dissolve the
product. The catalyst was separated by filtration and the filtrate
was washed with brine and dried over anhydrous Na2SO4. The
product was obtained after removal of the organic fractions using a
rotary evaporator. The desired pure products were further purified
by preparative TLC. All the products except 4i, 4r, 4s, 4w, 4x, 4y and
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In conclusion, a new carboxymethylcellulose-supported Cu(II)
catalyst has been synthesized, characterized, and used as an
inexpensive, renewable and biodegradable catalyst for three-
component coupling reaction of amines, aldehydes, and
phenylacetylene. A variety of aldehydes, amines and alkynes
proceed smoothly in the absence of solvent, any co-catalyst, other
additive, and base under aerobic conditions and excellent yields
were obtained. The catalyst was recycled for four consecutive runs.
The CMC-CuII catalyst can be regarded as an environmentally
benign catalyst, which is derived from the advantages of cellulosic
derivatives and the high catalytic activity in A3 couplings, as well as
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (Nos. 21372099 and 21301070), the Guangdong Natural
Science Foundation (Nos. 10151063201000051 and
8151063201000016) for financial support.
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Notes and reference
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9

RSC Advances
Page 10 of 10
View Article Online
DOI: 10.1039/C6RA18742K
Graphical Abstract
Copper(II) carboxymethylcellulose (CMC-CuII) as an efficient catalyst for
Aldehyde-Alkyne-Amine coupling under solvent-free conditions
Xiaoping Liu, Bijin Lin, Zhuan Zhang, Hao Lei and Yiqun Li*
R1CHO
R2
R1
R3
N
R2R3NH
R4
R4
Cu(II) carboxymethylcellulose
A novel heterogeneous Cu(II) carboxymethylcellulose catalyst was prepared and successfully
employed in the A3 coupling without using any co-catalyst, other additives, bases under
solvent-free conditions.