A highly efficient three-component coupling of aldehyde, terminal alkyne, and amine via C-H activation catalyzed by reusable immobilized copper in organic-inorganic hybrid materials under solvent-free reaction conditions

Article abstract of DOI:10.1016/j.tet.2007.04.032

Recycling copper(I) immobilized on organic-inorganic hybrid material behaves as a very efficient heterogeneous catalyst in the three-component Mannich coupling reaction of aldehydes, terminal alkynes, and amines via C-H activation to afford the correspond

Full text of DOI:10.1016/j.tet.2007.04.032

Tetrahedron 63 (2007) 5455–5459
A highly efficient three-component coupling of aldehyde, terminal
alkyne, and amine via C–H activation catalyzed by reusable
immobilized copper in organic–inorganic hybrid materials
under solvent-free reaction conditions
Pinhua Lia and Lei Wanga,b,
*
aDepartment of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui 235000, PR China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, PR China
Received 15 February 2007; revised 10 April 2007; accepted 12 April 2007
Available online 19 April 2007
Abstract—Recycling copper(I) immobilized on organic–inorganic hybrid material behaves as a very efficient heterogeneous catalyst in the
three-component Mannich coupling reaction of aldehydes, terminal alkynes, and amines via C–H activation to afford the corresponding
products in good to excellent yields under solvent-free reaction conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
on a resin. Subsequently, a microwave-assisted Mannich
three-component coupling reaction in the presence of
Cu(I) on Al2O3 was reported under solvent-free reaction
conditions by Kabalka et al.7 or in water by Tu et al.8 Within
the past few years, several noble transition-metal salts or
their bimetallic systems, such as Au,9 Ag,10 Ir,11 Ru–Cu,12
Ru–In13 were used by Li et al., for C–H activation to pro-
mote the Mannich three-component coupling reaction under
homogeneous conditions. Moreover, some of the reactions
were carried out in water,8,9,10a ionic liquids,10b,14 solvent-
Propargylamines are versatile intermediates for organic syn-
thesis1 and important structural elements of natural products
and potential drug molecules.1d,2 Traditionally, these com-
pounds are synthesized by nucleophilic attack of lithium
acetylides or Grignard reagents to imines or their deriva-
tives.3 However, these reagents are stoichiometric and
highly moisture sensitive. In addition, the reactions require
strictly controlled reaction conditions and sensitive func-
tionalities such as esters are not tolerated. The most at-
tractive synthetic method has been the Mannich one-pot
three-component coupling reaction of formaldehyde,
secondary amines, and terminal alkynes that was initially re-
stricted to arylacetylene.4 However, rather harsh conditions,
moderate yields, complex workup, and purification proce-
dures have limited its wider application. Since the last
decade, there has been a continuing interest in developing
transition-metal catalyst to accomplish the Mannich three-
component reaction via C–H bond activation.5 Dax et al. re-
ported the usage of copper as a transition-metal catalyst for
a solid-phase Mannich condensation of amines, aldehydes,
and alkynes.6 This polymer-supported three-component
Mannich reaction requires one of the reactants immobilized
less,7 or supercritical CO2 to meet the need of environ-
15
mental benign chemistry. Most recently, enantioselective
syntheses of propargylamines through one-pot three-
component condensation reactions have been developed.16
However, there are some limitations to the methods men-
tioned above: (i) the polymer-supported Cu(I)-catalyzed
method could not easily generate simple propargylamines
that had other functional groups; (ii) the microwave-assisted
method under solventless reaction conditions was limited to
the aminomethylation of alkynes and excess CuI was used;
(iii) Ir(I)-catalyzed method was limited to silylacetylenes;
(iv) Cu/Ru-catalyzed method was limited to imines gener-
ated from aryl amines and aryl aldehydes; (v) Ag-catalyzed
method was limited to aliphatic aldehydes; (vi) an expensive
metal catalyst (silver, gold, etc.) was often lost at the end of
the reaction when the catalysis was carried out in water or
organic solvent.
Keywords: Mannich three-component coupling; Aldehyde; Terminal
alkyne; Propargylamine; Immobilized copper catalyst; Organic–inorganic
hybrid materials; Solvent-free.
It should be noted that recently, Mannich three-component
reactions have been reported by Choudary et al., using
* Corresponding author. Tel.: +86 561 380 2069; fax: +86 561 309 0518;
e-mail: leiwang@hbcnc.edu.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.032

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P. Li, L. Wang / Tetrahedron 63 (2007) 5455–5459
hydroxyapatite-supported copper catalyst,17 and by Kantam
et al., using layered double hydroxide-supported gold cata-
lyst,18 in CH3CN and THF, respectively. However, the cata-
lyst could be recycled only up to 3–5 times without loss of
activity and substrate was limited to aryl alkyne in Kantam’s
method. Despite the advantages of homogeneous metal cat-
alyst, difficulties in recovering the expensive catalyst from
the reaction mixture severely obstruct its wide use in indus-
try. The development of heterogeneous catalyst to replace
the homogeneous one for the production of fine chemicals
in industrial processes remains an active research area,19a
because heterogeneous catalyst is easy to separate, poten-
tially reusable, and environment friendly.19b Thus, devel-
opment of highly efficient and reusable heterogeneous
catalytic system is desirable for the preparation of propargyl-
amines through the classic Mannich reaction.
The silica gel immobilized copper catalyst was prepared ac-
cording to the four-step procedure summarized in Scheme 1.
To a round-bottomed flask, a commercially available silica
gel was slurried in a solution of trichloro[4-(chloromethyl)-
phenyl]silane in toluene. The suspension was stirred for 20 h
at 120 ꢀC under an inert atmosphere, then the silica was iso-
lated and washed subsequently with toluene, dichloro-
methane, and methanol, and dried at 80 ꢀC for 10 h under
reduced pressure. The above benzyl chloride functionalized
silica gel was subsequently reacted with 1,2-diaminocyclo-
hexane (cis and trans mixture) in the presence of Na2CO3
in toluene at 100 ꢀC for 18 h. After the organics were
filtered, the silica was washed with toluene, water, and
methanol and dried. The loading of the modified silica was
readily quantified via CHN microanalysis and found to be
1.04 mmol gꢁ1 of NH. This organic–inorganic hybrid mate-
rial then reacted with cuprous iodide in DMF at room tem-
perature for 5 h to generate the silica–CHDA–Cu catalyst
with 1.589 wt % of Cu.
2. Results and discussion
Most Recently, we have developed immobilization of palla-
dium and copper in organic–inorganic hybrid materials and
their applications in Sonogashira reaction and Ullmann di-
aryl etherification.20 In order to extend the application scope
of this kind of catalysts, here we wish to report a highly ef-
ficient three-component coupling reaction of aldehydes, ter-
minal alkynes, and amines via C–H activation catalyzed by
a reusable immobilized copper in organic–inorganic hybrid
materials under solvent-free reaction conditions. In compar-
ison with the above-mentioned methods, this new method
showed particular advantages: (i) recyclability of the cata-
lyst up to 15 times without significant loss of catalytic activ-
ity; (ii) use of readily available, cheap copper catalyst
without Au, Ag, or other additives; (iii) lower catalyst
loading (1 mol %); (iv) broad substrate applicability (both
aromatic and aliphatic aldehydes, both aromatic and ali-
phatic terminal alkynes, and both aromatic and aliphatic
amines); (v) high yields attained; (vi) solvent-free reaction
conditions; and (vii) simple and easy experimental
operation. In this paper, we will describe our experimental
results.
In an effort to develop a better catalytic system, several
metals immobilized in organic–inorganic hybrid materials
were screened in the Mannich three-component reaction
composed of phenylacetylene, piperidine, and para-form-
aldehyde (model reaction) and the results are summarized in
Table 1. The Mannich reaction could be catalyzed by either
silica-supported Cu(I), Ag(I), or Au(I) in the absence of
solvent. But silica-supported Pd(II) failed. Among the sup-
ported-catalysts tested, silica–CHDA–CuI was found to be
the superior (entries a–j, Table 1). So, silica-supported CuI
was used as catalyst in the following investigation for its
high efficiency, commercial availability, and lower price.
The solvents also play an important role in the Mannich re-
action. Polar solvents, such as DMSO, DMA, and DMF were
found to be highly suited for this reaction, while the less
polar solvents, such as toluene, afforded the product only
in very poor yields. It is interesting to note that under
solventless reaction conditions, the reaction also underwent
smoothly to generate the corresponding three-component
coupling products in excellent yields (entries a–o, Table 1).
H2N
OH
OH
OH
OH
OH
OH
O
O
O
O
O
O
H2N
(cis and trans)
Si
Si
CH2Cl
Cl3Si
CH2Cl
Toluene
CH2Cl
Toluene
Cu(I)
O
O
O
O
O
O
O
O
O
O
O
O
H
Si
H
N
N
Si
CuI
DMF
1
2
N
H
N
H
Si
Si
Silica-CHDA-Cu Cat.
R1
Silica-CHDA-Cu Cat.
Solventless
NHR2R3
R1CHO
+
R
H
+
R
NR2R3
Scheme 1.

P. Li, L. Wang / Tetrahedron 63 (2007) 5455–5459
5457
Table 1. Effect of catalyst and solvent on the Mannich reactiona
Table 2. Silica-supported copper-catalyzed Mannich reactiona
R1
O
Catalyst
Silica-CHDA-Cu
+
+
NH
R1CHO
R
+
+
NHR2R3
R
H
H
NR2R3
Solventless
N
1
2
3
4
Entry
Amine
Aldehyde
Alkyne
Yieldb
(%)
Entry
Catalyst
Solvent
Yieldb (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Silica–CHDA–CuI
Silica–CHDA–CuBr
Silica–CHDA–CuCl
Silica–CHDA–AgI
Silica–CHDA–AgBr
Silica–CHDA–AgNO3
Silica–CHDA–AgOTf
Silica–CHDA–AuI
Silica–CHDA–AuCl
Silica–CHDA–Pd(OAc)2
Silica–CHDA–CuI
Silica–CHDA–CuI
Silica–CHDA–CuI
Silica–CHDA–CuI
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
DMSO
95
93
89
87
88
81
91
85
88
0
O
O
O
O
O
O
a
b
c
d
e
f
95
NH
NH
H
H
H
H
H
H
H
H
H
H
H
H
85
O
F
F
Ph
Ph
HN
99
82c
85c
84
NH2
88
85
91
12
DMF
CH3CN
Toluene
NHCH3
a
Phenylacetylene (1.00 mmol), piperidine (1.00 mmol), and para-form-
aldehyde (1.00 mmol), silica-supported metal catalyst (containing
0.01 mmol of metal) in the solvent indicated in Table 1 with stirring at
80 ꢀC for 12 h.
Br
N
H
O
O
b
g
h
NH
NH
90
93
Isolated yields.
H
H
H
H
CH3
During the course of our further optimization of the reaction
conditions, when using 1 mol % loading of the silica-
supported copper, the reactions were generally completed
in a matter of hours, but the time in the absence of solvent,
as expected, was inversely proportional to the temperature.
A reaction temperature of 80 ꢀC was found to be optimal.
Thus, the optimized reaction conditions for the Mannich
reaction are the silica–CHDA–Cu (1 mol %) under solvent-
free conditions at 80 ꢀC for 12 h.
F
O
O
O
i
95
92
90
91
O
NH
Ph
H
H
H
H
H
j
HN
HN
Ph
Ph
k
l
Ph
H
O
O
O
NH
H
O
To examine the scope of this three-component coupling
reaction, we extended our studies to different combinations
of aldehydes, amines, and alkynes. As depicted in Table 2,
both aromatic and aliphatic aldehydes, including those bear-
ing functional groups such as alkyl, alkoxy, and chloro
substitutions were able to undergo the corresponding three-
component coupling reaction. Aryl aldehyde with electron-
withdrawing group (entry p, Table 2) reacted smoothly;
however, electron-rich groups bound to the benzene ring
such as 4-methoxybenzaldehyde and 4-methylbenzaldehyde
reduced the reactivity (entries q and r, Table 2). The reaction
of aryl aldehydes was also tolerant of ortho substitution and
led to the good yield of product (entry o, Table 2). The de-
creased yields for aliphatic aldehydes might be caused by
the trimerization of aliphatic aldehydes. Different amines
also have an effect on the reaction: besides the fact that di-
alkylamines reacted smoothly in these conditions, anilines
also formed the corresponding products also in good yields
(entries d and e, Table 2). Aromatic alkynes with different
substituents, such as alkyl, fluoro, bromo, and chloro groups,
also underwent the corresponding three-component cou-
pling reaction smoothly and generated the products in high
yields under the present reaction conditions (entries b, d, f,
h, and i, Table 2).
m
n
82
92
90
NH
NH
NH
H
O
H
O
Cl
o
O
O
H
O
p
q
Cl
96
83
NH
NH
H
O
CH3O
CH3
H
O
r
90
O
NH
H
a
Aldehyde (1.00 mmol), alkyne (1.00 mmol), amine (1.00 mmol), and
silica–CHDA–Cu catalyst (40 mg, contains 0.01 mmol of Cu) under
solvent-free at 80 ꢀC for 12 h.
Isolated yields.
Silica–CHDA–Cu catalyst (80 mg, contains 0.02 mmol of Cu) was used.
b
c
recycling the catalyst was investigated. Figure 1 showed
a summary of the results. It could be seen that the catalyst
remained active through at least 15 cycles. After the product
In order to enhance the efficiency of the solid-state Mannich
condensation catalyst and reduce waste, the possibility of

5458
P. Li, L. Wang / Tetrahedron 63 (2007) 5455–5459
a reflux condenser, 80 mL of concentrated H2SO4 and
15 mL of HNO3 were added and the mixture was heated in
oil bath at 140 ꢀC for 24 h. The solution was filtered and
the white powder was washed with distilled water until neu-
tral pH was attained. The solid was again washed with ace-
tone, methanol, and dichloromethane, and dried under
vacuum at 150 ꢀC for 48 h.
In a 50 mL round-bottom flask were introduced successively
20 mL of anhydrous toluene, 2.5 g of activated silica, and
1.0 g of trichloro[4-(chloromethyl)phenyl]silane. The solu-
tion was refluxed for 20 h at 120 ꢀC under an inert atmo-
sphere. The solution was filtered and the solid was washed
subsequently with toluene, dichloromethane, and methanol,
and dried under reduced pressure at 80 ꢀC for 10 h. The
material of 2.91 g was obtained. FTIR (KBr, n cmꢁ1):
nSi–O¼1092; nC–H¼3024. Anal. Found: C, 9.31; H, 1.21, cor-
responding to 1.12 mmol gꢁ1 of benzyl chloride groups
based on C percentage.
Figure 1. Yields obtained with recycled silica–CHDA–Cu catalyst.
was removed from the silica-supported catalyst using an
organic solvent, the catalyst was reused directly for the
next trial without further treatment.
3. Conclusion
To a 25 mL round-bottomed flask, 2.0 g of the above benzyl
chloride functionalized silica gel, 0.3 g of Na2CO3, 0.14 g of
1,2-diaminocyclohexane (cis and trans mixture), 10 mL of
toluene were added. The mixture was heated at 100 ꢀC for
18 h. After cooling, the organics were filtered; the solid
was washed thoroughly with toluene, water, and methanol,
and dried under vacuum at 60 ꢀC overnight. Solid of 2.02 g
was obtained. The loading of the modified silica was readily
quantified via CHN microanalysis and found to be
1.04 mmol gꢁ1 of NH based on N percentage. (Anal. Found:
C, 12.49; H, 1.69; N, 1.49.)
In conclusion, a highly efficient silica-supported copper-
catalyzed three-component coupling reaction of aldehydes,
alkynes, and amines via C–H activation has been developed
under solventless reaction conditions. The process was sim-
ple and generated a diverse range of propargylamines in ex-
cellent yields. The reaction was applicable to both aromatic
and aliphatic aldehydes, alkynes, and amines. The catalyst
could be readily recovered and reused, thus making this pro-
cedure more environmentally acceptable whilst no catalyst
leaching was observed.
To a 25 mL round-bottomed flask, 40 mg of CuI and 10 mL
of DMF were added. The suspension was stirred at room
temperature under an inert atmosphere for 1 h, and then
1 g of the above functionalized silica gel was added.
The mixture was stirred at room temperature for 5 h,
then the organics were filtered, the solid was washed thor-
oughly with DMF and methanol, and dried under vacuum
at 60 ꢀC overnight. Green powder of 1.02 g (silica–
CHDA–Cu catalyst) was obtained. Anal. by ICP (atomic
%): Cu, 1.589.
4. Experimental
4.1. General
Starting materials and solvents were purchased from com-
mon commercial sources and were used without additional
1
purification. H and 13C NMR spectra were recorded in
CDCl3 with tetramethylsilane as an internal standard at am-
bient temperature on a Bruker 250 or 300 FT spectrometer
operating at 250 MHz or 300 MHz for H and 62.5 MHz
1
4.3. The recyclability of the silica-supported copper
or 75 MHz for 13C, respectively. All spectra were calibrated
at d 7.26 or d 0.00 ppm for 1H and d 77.03 for 13C. GC/MS
data were obtained by using a Hewlett–Packard 6890 series
GC equipped with a 5973 mass selective detector. IR spectra
were obtained by using a Nicolet NEXUS 470 spectropho-
tometer. Reactions were performed in oven-dried glassware
under nitrogen using standard inert atmosphere techniques.
Flash column chromatography was performed on silica
gel, SiO2.
After carrying out the reaction, the mixture was vacuum
filtered using a sintered glass funnel and washed with
CH2Cl2 (5 mL), Et2O (5 mL), C2H5OH (5 mL), and hexane
(5 mL). After dried on oven, they can be reused directly
without further purification.
4.4. General Mannich procedure
Amine (1.00 mmol) and terminal alkyne (1.00 mmol) were
added to a mixture of silica–CHDA–Cu(I) catalyst (40 mg,
contains 0.01 mmol of Cu) and aldehyde (1.00 mmol)
contained in a clean, dry, 10 mL round-bottomed flask under
nitrogen atmosphere. The mixture was stirred at 80 ꢀC for
12 h on oil bath. After the reaction was completed and
cooled to the room temperature, ethyl acetate (2ꢂ5 mL)
was added and the slurry was stirred at room temperature
to ensure removal of the product from the surface of catalyst.
The mixture was vacuum filtered using a sintered glass
4.2. Preparation and characterization of the immobili-
zation of copper catalyst in organic–inorganic hybrid
materials
This catalyst was prepared in the following steps from com-
mercial silica.
Activation of silica: 10 g of silica (100–200 mesh, Aldrich)
was introduced in a round-bottom flask equipped with

P. Li, L. Wang / Tetrahedron 63 (2007) 5455–5459
5459
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Acknowledgements
We gratefully acknowledge financial support by the
National Natural Science Foundation of China (20572031,
20372024), the Excellent Scientist Foundation of Anhui
Province, China (No. 04046080), the Scientific Research
Foundation for the Returned Overseas Chinese Scholars,
State Education Ministry, China (No. 2002247), the
Excellent Young Teachers Program of MOE, China (No.
2024), and the Key Project of Science and Technology of
State Education Ministry, China (No. 0204069).
17. Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Sreedhar, B.
Tetrahedron Lett. 2004, 45, 7319.
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