Multicomponent synthesis of 1,2,3-triazoles in water catalyzed by silica-immobilized NHC-Cu(I)

Article abstract of DOI:10.1007/s10562-012-0880-7

1,2,3-Triazole derivatives were synthesized in one-pot procedure via three-component reaction between organic halides, aromatic alkynes and sodium azide in the presence of 0.5 mol% Silica-immobilized NHC-Cu(I) catalyst. The catalyst showed high catalytic activity and 1,4-regioselectivity for the [3 + 2] Huisgen cycloaddition in water as a green solvent. This procedure has advantages that without the need to handle organic azides because of they are generated in situ. The reaction has a broad scope and good to excellent yields were obtained. The catalyst was recycled six times without significant loss of activity. Graphical Abstract: 1,2,3-triazole derivatives were synthesized in one-pot procedure via three-component reaction between alkynes, alkyl halides, and sodium azide in the presence of 0.5 mol% Silica-immobilized NHC-Cu(I) catalyst. The catalyst could be readily recovered and reused for 6 cycles without significant loss of its activity[Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-012-0880-7

Catal Lett (2012) 142:1134–1140
DOI 10.1007/s10562-012-0880-7
Multicomponent Synthesis of 1,2,3-Triazoles in Water Catalyzed
by Silica-Immobilized NHC–Cu(I)
•
Li Wan Chun Cai
Received: 18 June 2012 / Accepted: 16 July 2012 / Published online: 28 July 2012
Ó Springer Science+Business Media, LLC 2012
Abstract 1,2,3-Triazole derivatives were synthesized in
one-pot procedure via three-component reaction between
organic halides, aromatic alkynes and sodium azide in the
presence of 0.5 mol% Silica-immobilized NHC–Cu(I) cat-
alyst. The catalyst showed high catalytic activity and
1,4-regioselectivity for the [3 ? 2] Huisgen cycloaddition
in water as a green solvent. This procedure has advantages
that without the need to handle organic azides because of
they are generated in situ. The reaction has a broad scope
and good to excellent yields were obtained. The catalyst
was recycled six times without significant loss of activity.
complexes are known, many of which have been success-
fully used in catalytic applications [7, 8]. In numerous
instances simple substitution reaction routes involving
replacement of phosphanes by NHC ligands leads to higher
catalytic activity as well as improved thermal stability of
the resulting organometallic complexes. The common
knowledge that NHC ligands should be considered as
simple r donors is being replaced by the idea that NHC
ligands are electronically much more flexible. Both filled
and empty p, p* orbitals on the NHC ring can be deeply
involved in the bonding to the metal. They can contribute
to stabilize electron-rich metals through a d ? p* back-
donation scheme, but they are so flexible that they can also
stabilize electron-deficient metals through a p ? d dona-
tion scheme [9, 10].
Keywords 1,2,3-Triazole Á Copper Á Water Á NHC ligand
1 Introduction
Click chemistry is a chemical philosophy introduced by
Sharpless in 2001, emphasizing reactions that generate
substances quickly and reliably by joining small units
together [11]. The copper(I) catalyzed Huisgen [3 ? 2]
dipolar cycloaddition (CuAAC) between alkynes and
azides has arguably become the most popular ligation
reaction that has found a wide application in polymer and
drug discovery, biology and advanced material science
[12–23]. Most of the reported copper(I) catalytic species
were prepared in situ by reduction of Cu(II) salts [14],
oxidation of Cu(0) metal [24], or Cu(II)/Cu(0) compro-
portionation [25]. Due to copper(I) salts are oxygen sen-
sitive, they are less used or require the employment of
amines as additives in the reaction [26]. In recent studies,
the CuAAC has been proven to be accelerated by
Cu(I) species supported by nitrogen [27], sulfur [28], and
polydentate ligands [29], since those serve both to protect
the copper(I) center from oxidation or disproportionation
and to enhance its catalytic activity. However, such sup-
ported copper(I) catalysts are not always easily prepared.
The application of N-heterocyclic carbene (NHC) ligands
represents one of the most important developments in the
field of metal-mediated catalysis over recent years and
valuable contributions have been made to a diversity of
reactions [1–3]. Due to metal–carbene complexes are often
more stable than similar metal–phosphine complexes [4,
5], NHC ligands have been used as alternatives to phos-
phines as ligands in a broad range of transition metal cat-
alysts owing to their special donor properties [6].
Additional advantages of NHC ligands over the classic
phosphines include easy preparation, easy derivatization
and low cost. As a result, a large variety of metal–NHC
L. Wan Á C. Cai (&)
Chemical Engineering College, Nanjing University of Science
& Technology, 200 Xiaolingwei, Nanjing 210094,
People’s Republic of China
e-mail: c.cai@mail.njust.edu.cn
123

Multicomponent Synthesis of 1,2,3-Triazoles
1135
Moreover, reusability of copper catalysts for the CuAAC is
scarcely studied because of the generally homogeneous
nature of these catalysts, which make their recovery and
recycling difficult. The catalysts only can be used for one
time in the homogeneous reaction, which thus caused the
waste of expensive transition metal complexes and the
contamination problem in the product. Li et al. [30]
reported a series of water soluble ammonium salt-tagged
NHC–Cu catalysts. Although water soluble catalysts can be
recycled from the reaction mixture by liquid–liquid sepa-
ration, the aqueous phase was easily contaminated by
organic compounds, which cause the loss of the catalysts’
activity. And the products were obtained by extraction
from the mixture and using a large amount of solvents,
which will increase the economic expense. Furthermore,
using water as reaction media is limited, because some
water-sensitive substrates can not be used in this system.
Moreover, high catalyst loading (5.0 mol%) was needed in
the system and the catalyst was prepared through multiple
steps from 2,6-diisopropylaniline. To avoid catalyst
leaching and reduce the contamination of the product,
activated carbon, silica-supported and other heterogeneous
copper catalyst were synthesized and applied successfully
to click reactions [31–35]. Recently, Wang et al. [36]
reported an efficient NHC–Cu(I) heterogeneous catalyst for
[3 ? 2] cycloaddition of organic azides and terminal
alkynes in the presence of 1 mol% Cu catalyst. Although
organic azides are generally stable against most reaction
conditions such as water and oxygen, isolation or purifi-
cation of organic azides or polyazides can be problematic
[32, 37–39]. Therefore, a procedure that avoids the isola-
tion of organic azides is desirable.
were obtained using a PE5300DV analyzer. Specific surface
areas and pore volumes of the samples were determined in a
Micromeritics ASAP-2000 automated nitrogen physisorp-
tion apparatus and calculated according to the BET method.
2.2 Preparation of 1-(2,4,6-Trimethylphenyl)-1H-
Imidazole [40]
2,4,6-trimethylaniline (6.8 g, 0.05 mol) in MeOH (25 mL)
was stirred with 30 % aqueous glyoxal (8.1 mL, 0.05 mol)
for 16 h at room temperature. A yellowish mixture was
formed. Then, NH4Cl (5.4 g, 0.1 mol) was added followed
by 37 % aqueous formaldehyde (8 mL, 0.1 mol). The
mixture was diluted with MeOH (200 mL) and the result-
ing mixture was refluxed for 1 h. H3PO4 (7 mL, 85 %) was
added over a period of 10 min. The resulting mixture was
then stirred at reflux for a further 6 h. After removal of the
solvent, the dark residue was poured onto ice (100 g) and
neutralized with aqueous 40 % KOH solution until pH 9.
The resulting mixture was extracted with EtOAc
(3 9 100 mL). The organic phases were combined and
washed with H2O, brine and dried with anhydrous Na2SO4.
The solvent was removed and the residue was chroma-
tographied on silica gel (petroleum ether/EtOAc) to afford
the pure solid product (3.8 g, 41 %).
1H NMR (500 MHz, CDCl3) d: 7.45 (s, 1H), 7.25 (s,
1H), 6.99 (s, 1H), 6.91 (s, 2H), 2.36 (s, 3H), 2.31 (s, 6H);
13C NMR (125 MHz, CDCl3) d: 137.8, 136.5, 134.4, 132.4,
128.5, 128.0, 119.1, 20.0, 16.3; Anal. (%) found (calcd): C
77.19 (77.38), H 7.56 (7.58), N 15.13 (15.04).
2.3 Preparation of 1-Mesityl-3-(3-
Herein, we report an efficient silica-immobilized
NHC–Cu(I) heterogeneous catalyst for the regioselective
generation of 1,4-disubstituted 1,2,3-triazoles in a three-com-
ponent reaction. Furthermore, the catalyst can be recovered
and recycled by simple filtration from the reaction solution and
reused several times without significant loss of activity.
Trimethoxysilypropyl)imidazolium Iodide [41]
3-Iodopropyltrimethoxysilane (6.4 g, 22 mmol) and diox-
ane (15 mL) were added under nitrogen to a Schlenk vessel
containing 1-(2,4,6-trimethylphenyl)-1H-imidazole (3.7 g,
20 mmol). The mixture was refluxed for 12 h, followed by
removal of the solvent under vacuum. Addition of pentane
(15 mL) gave the product as an oily brown solid. Solvent
was decanted and the product was dried in vacuum at
60 °C for 2 h (8.3 g, 90 %).
2 Experiment
2.1 General
1H NMR (500 MHz, CDCl3) d: 9.92 (s, 1H), 7.82 (s,
1H), 7.25 (s, 1H), 7.01 (s, 2H), 4.71 (t, 2H, J = 2.0 Hz),
3.57 (s, 9H), 2.34 (s, 3H), 2.09–2.08 (m, 8H), 0.70 (m, 2H);
13C NMR (125 MHz, CDCl3) d: 140.0, 135.6, 133.3,
129.7, 128.8, 123.7, 122.1, 66.0, 50.9, 23.8, 20.0, 17.0, 8.6.
Anal. (%) found (calcd): C 45.11 (45.28), H 6.29 (6.33),
N 5.90 (5.87).
All reagents were commercially available and used without
any further purification. The solvents were dried before use.
IR spectra were recorded in KBr disks with a Bomem
MB154S FT-IR spectrometer. 1H NMR and 13C NMR were
recorded on Bruker DRX 500 and tetramethylsilane (TMS)
was used as an internal reference. Elemental analyses were
performed on a Vario ELIII recorder. The ICP analysis data
IR (KBr) m 780, 1090, 1458, 1532, 1660, 1976, 2930,
3210.
123

1136
L. Wan, C. Cai
2.4 Preparation of Iodo-1-Mesityl-3-(3-
Trimethoxysilypropyl)imidazole-2-
Ylidenecopper(I)
comparison of their physical and spectroscopic data with those
described in the literature.
2.7 Recycling of the Silica-Immobilized Catalyst
In an oven-dried Schlenk flask, CuI (0.95 g, 5 mmol),
NaO-t-Bu (0.48 g, 5 mmol), 1-mesityl-3-(3-trimethoxysi-
lypropyl)imidazolium iodide (2.4 g, 5 mmol) and THF
(25 mL) were added. The resulting suspension was stirred
at room temperature for 20 h under nitrogen atmosphere.
The solvent was reduced to 5 mL and the addition of
pentane (15 mL) gave the copper complex as a grey-green
powder (2.5 g, 93 %), m. p. 148 °C (decomposed).
1H NMR (500 MHz, DMSO-d6) d: 7.63 (s, 1H), 7.37 (s,
1H), 6.99 (s, 2H), 4.12 (t, 2H, J = 5.0 Hz), 3.60 (s, 9H),
2.36 (s, 3H), 1.89 (s, 6H), 1.76 (s br, 2H), 0.59 (s br, 2H).
13C NMR (125 MHz, DMSO-d6) d: 181.6, 138.9, 134.2,
134.1, 128.2, 120.7, 119.9, 51.9, 50.2, 25.9, 21.5, 17.6, 7.5.
Anal. (%) found (calcd): C 39.99 (40.04), H 5.37 (5.41),
N 5.23 (5.19).
A seal tube was charged with benzyl chloride (1.0 mmol),
NaN3 (1.2 mmol), phenylacetylene (1.0 mmol), H2O
(2 mL) and the catalyst (0.5 mol% Cu). The mixture was
stirred at 80 °C for 6 h. After the reaction was completed,
the catalyst was filtrated and the residue was washed with
EtOAc (3 9 3 mL), water (3 9 3 mL) respectively. Then
the catalyst was dried at 60 °C for 2 h for next cycle.
3 Results and Discussion
The copper catalyst immobilized on silica gel was readily
prepared in a three-step procedure as shown in Scheme 1.
1-(2,4,6-trimethylphenyl)-1H-imidazole was synthesized
according to the previous literature. In a general procedure,
compound 1 was refluxed with 3-iodopropyltrimethox-
ysilane in 1,4-dioxane under nitrogen atmosphere for 12 h,
then separated the product from the reaction mixture and
washed with pentane to obtain compound 2. The ionic
liquid 2 reacted with CuI in the presence of NaO-t-Bu in
dry THF at room temperature under nitrogen atmosphere.
Immobilization of complex 3 in the silica gel was carried
out in DMF at 120 °C for 12 h. The copper metal amount
of the immobilized catalyst was found to be
0.096 mmol g-1 based on ICP analysis. After immobili-
zation of NHC–Cu(I), the surface area of silica gel
decreased from 546 to 419 m2 g-1 and the average pore
volume decreased from 0.76 to 0.65 cm3 g-1 due to the
loading of the NHC–Cu(I) complex.
IR (KBr) m 760, 1100, 1430, 1554, 1660, 1710, 1976,
3100.
2.5 Preparation of Silica-Immobilized NHC–
Cu(I) Catalyst
The solution of NHC–Cu(I) complex (108 mg, 0.2 mmol) in
dimethylformamide (DMF) (2 mL) was added to a well-
stirred DMF suspension (40 mL) of mesoporous silica gel
˚
(2 g, average pore diameter 60 A, 70–230 mesh, dried at
500 °C for 12 h before use). The mixture was stirred at
120 °C for 12 h. The solid was filtered off and washed with
hot DMF to remove the remaining non-supported complex
from the heterogenized catalyst, and then washed subse-
quently with water, ethanol and dried under reduced pressure
at 80 °C for 6 h. The copper metal amount of the catalyst was
found to be 0.096 mmol g-1 based on ICP analysis. The
surface area and pore volume of the catalyst were found to be
419 m2 g-1 and 0.65 cm3 g-1 respectively.
To investigate the catalytic activity of the silica-immo-
bilized NHC–Cu(I), the 1,3-dipolar cycloaddition reaction
between benzyl chloride, NaN3 and phenylacetylene was
chosen as the model reaction (Table 1). During our optimi-
zation studies, various solvents were examined and it was
found that the solvent plays a significant role in terms of
reaction rate, isolated yield, and selectivity. Among the
solvents tested in Table 1, DMF, DMSO, toluene, CH2Cl2,
CH3CN were gave very low product yield (Table 1, entries
1–5), because of their poor solubility of NaN3. Although the
reaction in methanol gave the highest yield, water clearly
stands out as the solvent of choice with its fast reaction rate,
high yield, selectivity, cheapness, green solvent nature and
environmental acceptability (Table 1, entries 6 and 8).
However, only trace amount of the product was detected by
GC–MS when the reaction was carried out under neat reac-
tion conditions (Table 1, entry 13). Catalyst loading and
reaction temperature also affected the reaction, and in our
work, 0.5 mol% of the catalyst is sufficient to catalyze the
2.6 General Procedure for Three-Component 1,3-
Dipolar Cycloaddition Catalyzed by Silica-
Immobilized NHC–Cu(I) Catalyst in Water
A seal tube was charged with halide (1.0 mmol), NaN3
(1.2 mmol), substituted phenylacetylene (1.0 mmol), H2O
(2 mL) and the catalyst(0.5 mol%Cu). The mixture was stirred
at 80 °C for a certain time. After the reaction was completed,
the resulting mixture was extracted with EtOAc (3 9 3 mL).
The collected organic phases were dried with anhydrous
Na2SO4 and the solvent was removed under vacuum to give the
corresponding triazole, the product was further purified by flash
chromatography with petroleum ether/EtOAc as eluent. All the
products were known compounds and were characterized by
123

Multicomponent Synthesis of 1,2,3-Triazoles
1137
Scheme 1 Synthesis and immobilization of the copper carbene catalyst
Table 1 Optimization of the Click reaction conditions
SiO2-NHC-Cu(I)
Cl
+
NaN3 +
N
N
solvent
N
Entry
Solvent
Temperature (oC)
Catalyst Loading (mol%)
Time (h)
Yielda (%)
1
DMF
DMSO
Toluene
CH2Cl2
CH3CN
MeOH
EtOH
H2O
70
70
70
70
70
70
70
70
50
80
80
80
80
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
0.1
0.5
6
6
6
6
6
6
6
6
6
6
6
6
6
21
19
0
2
3
4
0
5
13
94
89
92
58
96
98
39
Trace
6
7
8
9
H2O
10
11
12
13
H2O
H2O
H2O
Neat
Reaction conditions: benzyl chloride (1.0 mmol), NaN3 (1.2 mmol), phenylacetylene (1.0 mmol), catalyst (0.5 mol% Cu) in 2 mL solvent
a
Isolated yield
reaction successfully (Table 1, entries 10–12). Lowering the
temperature to 50 °C caused drastic decrease of the yield
(Table 1, entry 9).
entries 7–8). Next, we used various substituted benzyl
chlorides to screen aromatic alkynes (Table 2, entries
9–14). It was found that the starting materials containing
electron-donating groups gave the products in lower yield.
Moreover, reaction time was prolonged to 9 h when using
p-methoxybenzyl chloride in the Huisgen [3 ? 2] cyclo-
addition, because of its low reactivity. As can be seen from
Table 2, the reactions involving organic bromo compounds
lead to the corresponding 1,4-disubstituted 1,2,3-triazoles
in higher yields (Table 2, entries 15–18) and bromocyclo-
hexane gave the product in 82 % yield (Table 2, entry 19).
3-bromo-1-propyne was investigated in this system, how-
ever, only trace of the product was obtained.
To examine the generality of the reaction, we extended
our studies to a variety of organic halides and aromatic
alkynes to generate the corresponding 1,4-disubstituted
1,2,3-triazoles. Firstly, we screened the reactivity of benzyl
chloride and its derivatives under the optimized conditions.
As shown in Table 2, substituted benzyl chlorides con-
taining both electron-donating and electron-withdrawing
groups in the para position afforded the products in
excellent yields. And benzyl chlorides bearing electron-
donating group gave the 1,2,3-triazoles in slightly lower
yield (Table 2, entries 2–6). It is noteworthy that the
position of the substituted groups affects the reaction dra-
matically and only moderate yields were obtained (Table 2,
The recyclability of silica-immobilized NHC–Cu(I) cat-
alyst was tested in the cycloaddition of benzyl chloride,
NaN3 and phenylacetylene under the optimized reaction
123

1138
L. Wan, C. Cai
Table 2 One pot synthesis of triazoles from halides, terminal alkyne and sodium azide
R2
0.5 mol % Cu
R1 X + NaN3 + R2
H2O, 80oC
N
N
R1
N
Entry
1
Organic Halide
R2
H
Time (h)
6
Yielda (%)
96
Cl
2
H
6
90
Cl
H3C
3
4
H
H
6
6
87
93
Cl
Cl
MeO
O2N
5
6
7
H
H
H
6
6
6
98
95
53
Cl
NC
F
Cl
Cl
CH3
8
H
6
76
9
4-CH3
4-F
6
6
9
83
89
76
10
11
4-CH3
12
4-F
9
85
123

Multicomponent Synthesis of 1,2,3-Triazoles
1139
Table 2 continued
Entry
13
Organic Halide
R2
Time (h)
6
Yielda (%)
88
4-CH3
14
4-F
6
95
15
16
H
H
6
6
98
93
17
18
19
H
H
H
6
6
6
90
86
82
Reaction conditions: halide (1.0 mmol), NaN3 (1.2 mmol), substituted phenylacetylene (1.0 mmol), catalyst (0.5 mol% Cu) in 2 mL H2O at
80 °C
a
Isolated yield
100
80
60
40
20
0
cycles without significant loss of activity (Fig. 1). Mean-
while, copper leaching in the reaction was detected by ICP
analysis. The filtrates obtained by filtration after the reac-
tion indicated that Cu content was \0.6 ppm. However,
only trace amount of the desired product was detected by
GC–MS for the model reaction by adding substrates to a
filtrate obtained from the filtration of the immobilized
catalyst after the reaction.
85
84
92
90
87
90
4 Conclusions
1
2
3
4
5
6
Cycle
Fig. 1 Recyclability of the catalytic system
In summary, an efficient and green one-pot synthesis of
1,4-disubstituted 1,2,3-triazoles from organic halides,
NaN3 and aromatic alkynes catalyzed by silica-immobi-
lized NHC–Cu(I) has been developed. The reactions pro-
ceeded smoothly to generate the corresponding products in
high yields. In addition, the catalyst could be readily
recovered and reused for 6 cycles without significant loss
conditions. After the reaction, the catalyst was separated by
simple filtration and washed with EtOAc and water. After
being dried, it could be reused directly without further
purification. The catalyst could be recycled in six repetitive
123

1140
L. Wan, C. Cai
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