Nano-copper catalyzed three-component reaction to construct 1,4-substituted 1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2014.02.114

Three-component reaction of alkyl halides, sodium azide with terminal alkynes can be catalyzed by nano-copper particles under ambient conditions. A series of 1,4-disubstituted-1,2,3-triazoles were obtained regioselectively by this one-pot strategy. Nano c

Full text of DOI:10.1016/j.tetlet.2014.02.114

Tetrahedron Letters 55 (2014) 2312–2316
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nano-copper catalyzed three-component reaction to construct
1,4-substituted 1,2,3-triazoles
⇑
⇑
Lina Huang, Wei Liu, Juncheng Wu, Ying Fu, Kehu Wang, Congde Huo , Zhengyin Du
Key Laboratory of Eco-Environment Related Polymer Materials of Ministry of Education, Key Laboratory of Polymer Materials of Gansu Province, College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou 730070, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Three-component reaction of alkyl halides, sodium azide with terminal alkynes can be catalyzed by
nano-copper particles under ambient conditions. A series of 1,4-disubstituted-1,2,3-triazoles were
obtained regioselectively by this one-pot strategy. Nano copper can be reused at least three times
without significant deactivation.
Received 20 December 2013
Revised 18 February 2014
Accepted 27 February 2014
Available online 6 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Copper nanoparticles
Phenylacetylene
Cycloaddition
Click chemistry
Multicomponent reaction
At the dawn of the 21st century, green catalysis, including using
highly efficient catalyst, clean solvent, multicomponent reaction,
and recoverable reaction system, has become a hot topic in chem-
ical transformations and has been paid more attention by
researchers.1,2
copper catalysts such as Cu2O,16 CuI,17,18 CuSO4,19–21 CuBr
(PPh3)3,22 CuFe2O4 nanoparticles,1 and polymeric imidazole-
Cu(II).23 Supported Cu(0) nanoparticles were also used as a catalyst
in this reaction, such as Cu–Fe bimetals for two-component
reaction,24 Cu/SiO2,25 Cu/C,26 and polymer capped Cu/Cu2O27 for
three-component reaction. Copper nanoclusters have already been
In many transition metals, copper has been used as catalyst in
organic synthesis for many decades.3–6 The discovery of
Cu(I)-catalyzed azideÀalkyne cycloaddition yielding selectively
1,4-disubstituted-1,2,3-triazoles is a very important advance in
the chemistry of triazoles.7,8 As we know, 1,2,3-triazoles are impor-
tant building blocks of nitrogen heterocyclic compounds and have
been widely used in pharmaceuticals, agro chemicals, dyes, photo-
graphic materials, corrosion inhibition, etc.9 1,2,3-Triazoles are
also associated with a wide range of biological properties such as
magnetic resonance imaging, drug delivery, and biomolecular
sensors.10 Two routes are generally adopted for the synthesis of
substituted 1,2,3-triazoles. One is copper catalyzed [3+2] cycload-
dition of organoazides with alkynes. However, methods for the
preparation of organic azides are rather limited.11 Moreover, it
needs two-step reactions, special reagents, even strictly oxygen,
and water-free conditions to obtain the aimed products via organic
azides.12–15 In order to overcome the disadvantages of the above
two-step reactions, one pot, three-component reaction of alkyl
halides, sodium azide, and alkynes is developed recently by using
⇑
Corresponding authors. Tel.: +86 931 797 1533; fax: +86 931 797 1989.
E-mail address: clinton_du@126.com (Z. Du).
Figure 1. SEM micrograph of Cu NPs.
http://dx.doi.org/10.1016/j.tetlet.2014.02.114
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

L. Huang et al. / Tetrahedron Letters 55 (2014) 2312–2316
2313
Table 1
Screening of the catalyst for the three-component click reactiona
Entry
Catalyst
Yield b(%)
1
2
3
4
5
6
CuBr
CuI
CuCl2
70
83
82
83
62
93
45
85
91
CuSO4Á5H2O
CuO
Cu NPs
Cu powder
Cu NPs
Cu NPs
7
8c
9d
a
Reaction conditions: phenylacetylene (0.5 mmol), benzyl bromide (0.6 mmol), NaN3 (0.6 mmol), catalyst
(0.025 mmol), methanol (2 mL), r.t.
b
Isolated yield.
Catalyst (0.01 mmol).
Catalyst (0.05 mmol).
c
d
Table 2
Cu NP catalyzed cycloaddition of phenylacetylenes, benzyl halides, and sodium azidea
Entry
Alkyne
Benzyl halide
Product
Time (h)
8
Yieldb (%)
N
N
N
Br
1
93
86
82
71
88
90
N
N
N
N
N
N
Cl
2
3
4
5
6
10
12
14
12
12
N
F
N
Cl
F
N
O2N
Me
N
Br
NO2
N
N
Cl
Me
N
N
Me
Me
N
Br
Me
Me
F
F
Cl
N
N
7
12
80
N
Me
Me
NO2
Me
O2N
Br
N
N
8
9
16
12
69
81
N
Me
N
N
Me
Me
N
Cl
Me
Me
(continued on next page)

2314
L. Huang et al. / Tetrahedron Letters 55 (2014) 2312–2316
Table 2 (continued)
Entry
Alkyne
Benzyl halide
Product
Time (h)
12
Yieldb (%)
72
N
N
N
N
F
F
F
N
Br
10
F
N
Me
F
N
Cl
11
12
12
14
77
55
Me
F
N
N
Cl
F
F
H2N
Me
Me
Me
Cl
Me
N
13c
14
82
N
N
N
a
b
c
Reaction conditions: phenylacetylenes (0.5 mmol), benzyl halides (0.6 mmol), NaN3 (0.6 mmol), Cu NPs (0.025 mmol), methanol (2 mL), r.t.
Isolated yield.
Yield was calculated with 4-methylbenzyl chloride as benchmark.
Table 3
Cu NP catalyzed cycloaddition of phenylacetylenes, alkyl bromides, and sodium azidea
Entry
1
Alkyne
Alkyl bromide
Product
Time (h)
14
Yieldb (%)
69
N
N
Br
N
Br
N
2
14
62
N
N
N
N
Br
N
3
4
5
6
7
8
14
14
14
14
14
14
56
58
56
60
59
60
N
N
Br
N
N
N
Me
Me
Me
Me
F
Br
N
Me
Me
Me
Me
N
N
N
N
Br
N
N
Br
N
N
Br
Br
N
N
N
Br
N
9
16
55
F
F
N
N
F
N
10
11
16
14
66
85
N
N
Br
N
a
Reaction conditions: phenylacetylenes (0.5 mmol), alkyl bromides (0.6 mmol), NaN3 (0.6 mmol), Cu NPs (0.025 mmol), methanol (2 mL), r.t.
Isolated yield.
b

L. Huang et al. / Tetrahedron Letters 55 (2014) 2312–2316
2315
Table 4
Reusability of Cu NPs
The results are shown in Table 1. We found that all of Cu(I) and
Cu(II) salts could effectively catalyze the click reaction of benzene-
acetylene, benzyl bromide, and sodium azide to obtain 1-benzyl-4-
phenyl-1H-1,2,3-triazole exclusively in good yields in methanol at
room temperature (Table 1, entries 1–5). When Cu NPs were used,
excellent yield (93%) was achieved at the same amount of catalysts
(5 mol %, Table 1, entry 6). However, when commercially available
Cu powder was explored, only 45% yield was given (Table 1, entry
7). This illustrates that the particle size and surface properties
played an essential role in this transformation. Then we studied
the loading of Cu NPs and the results show that 5 mol % of Cu
NPs is the optimized dosage (Table 1, entries 6, 8 and 9). It is note-
worthy that the side-product of 4-phenyl-1H-1,2,3-triazole and the
isomer of 1-benzyl-5-phenyl-1H-1,2,3-triazole were not found in
the three-component reaction.
Under the optimized conditions, different substituted phenyl-
acetylenes and benzyl halides were used in this click reaction and
an array of 1,4-disusbstituted 1,2,3-triazoles were synthesized
smoothly in good to excellent yields.29 These results are presented
in Table 2. Phenylacetylenes and benzyl halides containing hydro-
gen and electron-donating groups at the aryl ring worked well un-
der these conditions, producing the corresponding products in good
to excellent yields. Phenylacetylenes and benzyl halides bearing
Cycle
Yield (%)
Native
93
91
88
87
1
2
3
documented as a catalyst for the reaction of organic azides with
alkynes.28 However, to date, no literature was involved in Cu nano-
particle (NP) catalyzed three-component reaction without the use
of any support and stabilizer. Herein, we report a simple and
efficient three-component [3+2] cycloaddition of organic halides,
terminal alkynes, and sodium azide to yield 1,4-disubstituted-
1,2,3-triazoles catalyzed by Cu NPs under ambient conditions.
The Copper nanoparticles were prepared by reducing copper
sulfate pentahydrate with hydrazine hydrate in ethylene glycol.
This method gives a stable Cu NPs with a narrow particle size
distribution that can be kept for several months in air. SEM micro-
graph showed that the average dimension of Cu NPs was around
18–23 nm (Fig. 1).
In our initial study, we chose benzeneacetylene, benzyl
bromide, and sodium azide to optimize the reaction conditions.
N
N
N
NaN3
(5 mol%) Cu NPs
Br
N3
(1)
(5 mol%) Cu NPs
CH3OH, RT
CH3OH, RT
Yield: 85%
Br
N
N
N
NaN3
(5 mol%) Cu NPs
N
N
(2)
NH
CH3OH, RT
(5 mol%) Cu NPs
CH3OH, RT
Yield: 0%
Scheme 1. Exploration of the reaction process.
R1
R2
N
N
N
R1
R1
R2
N
H
Cu NPs
R2
N
N
Cu
N
R1
H
N
R1
N
III
R1
H+
H+
Cu
H+
R2
N
R1
N
H
Cu
N
R1
I
II
R1
R2-X NaN3
R2
N
N
N
Scheme 2. Proposed mechanism.

2316
L. Huang et al. / Tetrahedron Letters 55 (2014) 2312–2316
electron-withdrawing groups could also obtain corresponding
products in relatively low yields.
Supplementary data
Supplementary data (the 1H NMR, 13C NMR, IR, MS spectro-
scopic data, elemental analysis and NMR spectra of all products)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.02.114.
It is interesting that when electron-rich 4-methylphenylacety-
lene and electron-deficient benzyl halides were used in this cyclo-
addition reaction, 1,2,3-triazoles with an alkynyl substituent at
5-position were obtained in good yields (Table 2, entries 7 and
8). The results are in accord with literature reported,16 which
might result from an oxidizing addition of copper and reductive
elimination subsequently under ambient conditions. When
3-aminophenylacetylene reacted with 4-methylbenzyl chloride
and sodium azide, a novel product N,N-di(4-methylbenzyl) 1,2,
3-triazole was formed in 82% of yield (Table 2, entry 13).
Various alkyl bromides were subjected to the same reaction
conditions to furnish the corresponding 1,2,3-triazole derivatives
and the results are listed in Table 3. The yields were moderate in
general. The length of alkyl chain did not manifestly affect the yield
of the product. When bulky tert-butyl bromide was used, the yields
were 55–69% (Table 3, entries 1, 5, and 9). This shows that steric
hindrance of alkyl bromides has also no significant effect on the
reaction. Unfortunately, aliphatic alkynes gave no designed prod-
uct under the same conditions.
References and notes
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At last, the reusability of Cu NPs was examined by the model
reaction of phenylacetylene, benzyl bromide, and sodium azide
and the results are given in Table 4. It can be showed that after
three recycles, the product yield was still up to 87%, which indi-
cates that Cu NPs have high catalytic activity and stability in our
experimental conditions (Table 4).
In order to clarify the mechanism of this multicomponent reac-
tion, we conducted two stepwise control experiments as shown in
Scheme 1. The result showed that the yield of 1-benzyl-4-phenyl-
1,2,3-triazole of this two-step process was slightly inferior to
three-component reaction (85% of Scheme 1, Eq. 1 vs 93% of Table 2,
entry 1). But, is it possible that phenyl acetylene clicked with so-
dium azides to get 4-phenyl-1,2,3-triazole and then underwent a
N-alkylation with alkyl halides? Unfortunately, no target molecule
was formed under the same reaction conditions (Scheme 1, Eq. 2).
Therefore, we think that the one-pot, three-component reaction is
virtually a two-step procedure. Organic halides firstly reacted with
sodium azide to obtain organic azides, and then further converted
into final products with alkynes catalyzed by nano copper.
Based on the above control experiments, a possible mechanism
was proposed in Scheme 2. Alkynes are converted to alkynyl cop-
per(I) in the presence of Cu NPs first. Then, intermediate (I) reacts
with organic azides formed in situ by click chemistry to yield the
key intermediate (II). Intermediate (II) is further transformed into
1,4-disubstituted 1,2,3-triazoles or 5-alkynyl-1,4-disubstituted
1,2,3-triazoles via intermediate (III).
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29. General procedure for the synthesis of 1,4-disubstituted 1,2,3-triazoles: Sodium
azide (0.6 mmol), organic halides (0.6 mmol), and phenylacetylenes
(0.5 mmol) were added into
a suspension of 0.025 mmol of Cu NPs in
In conclusion, we have developed a simple and highly efficient
one-pot method to synthesize complex 1,2,3-triazoles regioselec-
tively from organic halides, terminal alkynes, and sodium azide.
The reactions were performed under ambient conditions in meth-
anol at room temperature, using Cu NPs as catalysts. Simple oper-
ation, air atmosphere, easy separation, and reusability of Cu NPs
are the salient features of this method.
methanol (2 ml). The reaction mixture was stirred at room temperature for
completion monitored by TLC. Then the solution was filtered by suction and
the solvent was evaporated under reduced pressure. The residue was passed
through flash column chromatography on silica gel to give the pure products.
The characterization data of representative products are as follows. 4-Phenyl-5-
(2-phenylethynyl)-1-propyl-1H-1,2,3-triazole: white solid, mp 85–86 °C; 1H
NMR (400 MHz, CDCl3) d = 1.06–1.10 (t, 3H), 2.09–2.15 (m, 2H), 4.51–4.54 (t,
2H), 7.41–7.54 (m, 6H), 7.62–7.64 (m, 2H), 8.25–8.27 (d, 2H); 13C NMR
(100 MHz, CDCl3) d = 148.00, 131.81, 130.70, 129.91, 128.95, 128.92, 128.75,
126.45, 121.78, 117.44, 102.08, 75.79, 51.06, 23.57, 11.41; MS (EI) m/z (%) 287
[M]+; IR (KBr, cmÀ1): 3062, 2852, 1620, 1478, 1359, 755, 690; Anal. Calcd for
Acknowledgments
C
19H17N3 (287.36): C 79.41, H 5.96, N 14.63, Found C 79.37, H 5.91, N 14.60. 1-
tert-Butyl-4-(4-fluorophenyl)-1H-1,2,3-triazole: white solid, mp 141–142 °C; 1H
NMR (400 MHz, CDCl3) d = 7.96 (s, 1H), 7.82–7.86 (m, 1H), 7.30 (s, 2H), 7.16–
7.21 (t, 2H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) d = 160.09, 131.33, 127.49,
127.41, 115.67, 115.45, 30.25, 29.27; MS (EI) m/z (%) 163 [M]+; IR (KBr, cmÀ1):
3040, 2853, 1611, 1367, 1238, 773, 687; Anal. Calcd for C12H14FN3 (219.26): C
65.73, H 6.44, N 19.16, Found C 65.75, H 6.43, N 19.19.
We gratefully acknowledge the Natural Science Foundation of
China (20702042, 21262028), the Program for Changjiang Scholars
and Innovative Research Teams in Universities of the Ministry of
Education of China (IRT1177), the Natural Science Foundation of
Gansu Province (1208RJZA140) for financial support.