Porous copper catalyzed click reaction in water

Article abstract of DOI:10.1039/c3nj00468f

1,2,3-Triazoles were synthesized in water using a cheaper, simple and easily recyclable heterogeneous porous Cu catalyst via one-pot multi component reaction. The catalyst can be recycled five times without significant loss of its catalytic activity.

Full text of DOI:10.1039/c3nj00468f

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Porous copper catalyzed click reaction in water†
Chen Zhang,*a Bo Huang,a Ying Chenb and Dong-Mei Cui*b
Cite this: DOI: 10.1039/c3nj00468f
Received (in Montpellier, France)
4th May 2013,
Accepted 14th June 2013
DOI: 10.1039/c3nj00468f
www.rsc.org/njc
1,2,3-Triazoles were synthesized in water using a cheaper, simple alkyl halides and sodium azide for direct cycloaddition with
and easily recyclable heterogeneous porous Cu catalyst via one-pot alkynes, alkyl halides, and sodium azide using porous copper.
multi component reaction. The catalyst can be recycled five times Porous metals that have a large surface-to-volume ratio, are
without significant loss of its catalytic activity.
light weight, and exhibit excellent electrical–thermal conduc-
tivity have attracted much attention because of a wide range of
The copper-catalyzed azide–alkyne cycloaddition (CuAAC), also applications in chemistry, mechanics, and nanotechnology.8
known as a ‘‘click reaction’’, has become one of the most Porous copper, which has excellent structural characteristics
important reactions for the preparation of 1,2,3-triazoles.1 This and is basically harmless to the human body, was mostly used
important reaction has found a wide range of applications in as filter material.
organic synthesis, bio- and medicinal chemistry, and materials
In an initial attempt to synthesize 1,2,3-triazoles using a
science.2 Most AAC protocols call for a homogeneous Cu(I) copper catalyzed procedure, we have investigated the cyclo-
source – either by direct addition of a Cu(I) salt, or by in situ addition reaction of sodium azide (1 mmol) with benzyl bromide
reduction of Cu(II) by sodium ascorbate.3 In recent years, due to (1a) (1 mmol) and phenylacetylene (2a) (1 mmol) in water as
their efficient recyclability and facile separation of products, solvent. Our catalytic system consists of commercially available
immobilized catalysts have attracted much attention in econo- sintered copper porous material. A systematic study was first
mical and environmentally benign chemical processes. In an undertaken to define the best reaction conditions, and the
effort to find immobilized copper catalysts, Cu(0) on charcoal,4 representative data obtained for the synthesis of 1,2,3-triazoles
Cu(0) nanoparticles,5 or Cu(0) nanoporous6 as well as with porous copper catalysts having various pores are listed in
microwave irradiated Cu turnings7 have also successfully Table 1. First of all, the reactions performed using porous copper
demonstrated activity for this reaction. The development of (5 mol%) with a size of about B5 mm proceeded efficiently to
heterogeneous immobilized catalysts that are inexpensive, form the corresponding triazole 3a in 96% isolated yield at 55 1C
easily available, easy to handle, reusable, and have high effi- (Table 1, entry 1). Efficient cycloaddition was realized with
ciencies for this purpose still remains a major challenge. On significantly lower catalyst loading, although it required a longer
the other hand, most of the reported CuAAC studies are on two- reaction time (Table 1, entry 3). A large decrease in yield was
component (organic azide and alkyne) reaction systems; the observed using the copper catalyst with larger pores (Table 1,
organic azides need to be synthesized in advance, and the entries 4–6). Compared to other screened solvents such as
potential hazards of organic azides especially in the isolation acetonitrile, THF, DMF, ethanol, acetone, dioxane, and toluene,
or the purification process can be problematic. It is thus water appeared to be the best one (Table 1, entries 1 and 7–13).
desirable to develop an efficient one-pot methodology that uses
With the optimal reaction conditions in hand, the scope of
the copper-catalyzed synthesis of 1,2,3-triazoles was explored.
The results are summarized in Table 2. In alkyl halides, benzyl
chloride can serve as a good substrate to afford the triazole
(Table 2, entry 2). Other aliphatic halides also reacted easily
with sodium azide and alkynes affording 3k and 3l in high
yields (Table 2, entries 12 and 13). Furthermore, to further
analyze the possible electronic effects and to expand the scope
of this method, acetylenes bearing aromatic groups of various
a School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058,
PR China. E-mail: chenzhang@zju.edu.cn; Fax: +86 0571 88208459;
Tel: +86 0571 88208459
b College of Pharmaceutical Science, Zhejiang University of Technology,
Hangzhou 310014, PR China. E-mail: cuidongmei@zjut.edu.cn;
Fax: +86 0571 88320320; Tel: +86 0571 88320320
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3nj00468f
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Table 1 Catalyst screening in the synthesis of 3aa
Table 3 Recycling of catalystsa
Entry
1
2
3
4
5
6
Yieldb (%)
96
95
100
99
98
94
a
The reactions were performed with 1a (1.0 mmol), 2a (1.1 mmol),
NaN3 (2.0 mol), and Cu catalyst (5 mol%) in H2O at 55 1C for 29 h.
Isolated yields.
b
Cu catalyst
size (mol%)
Time
(h)
Yield of
Entry
Solvent
3ac (%)
1
2
3
4
5
6
7
8
B5 mm (5)
B5 mm (10)
B5 mm (1)
B15 mm (5)
B50 mm (5)
B150 mm (5)
B5 mm (5)
B5 mm (5)
B5 mm (5)
B5 mm (5)
B5 mm (5)
B5 mm (5)
B5 mm (5)
B5 mm (5)
H2O
H2O
H2O
H2O
H2O
H2O
CH3CN
DMF
EtOH
Acetone
THF
29
10
42
29
55
85
30
53
30
30
55
69
29
30
96
95
90
87
66
27
10
28
45
59
5
of the first reaction, simple filtration of the reaction mixture,
the catalyst was washed with water and methanol and reused
without further purification. A new reaction was then per-
formed with fresh reactants, under the same conditions. We
showed that the catalyst can be reused five times without any
loss of activity. Examples of the reaction carried out using the
recovered catalyst are presented in Table 3. The yields of
triazole 3a were basically similar to those observed using a
fresh non-recycled copper catalyst.
In conclusion, a very efficient, sustainable and green proce-
dure for the one-pot synthesis of triazoles has been developed
using a cheaper, commercially available and easily recyclable
heterogeneous porous Cu catalyst in water. The copper catalyst
could be recycled in five subsequent reactions without the loss
of the reaction efficiency. A wide range of alkynes and alkyl
halides can be tolerated, giving the corresponding triazoles in
good yields.
9
10
11
12
13
14b
Dioxane
Toluene
H2O
5
0
33
a
The reactions were performed with 1a (1.0 mmol), 2a (1.1 mmol),
b
NaN3 (2.0 mol), and Cu catalyst (1–10 mol%) in solvent at 55 1C. rt.
c
Isolated yields.
Table 2 Cu Catalyzed synthesis of [1,2,3]-triazoles 3a
Experimental section
Unless otherwise noted, materials were obtained from commercial
suppliers and used without further purification. 1H NMR
(500 MHz) and 13C NMR (125 MHz) spectra were recorded on
a Bruker Avance spectrometer in CDCl3 with Me4Si as an
internal standard. Data were reported as follows: chemical shift
in ppm (d), multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, br = broad and m = multiplet), coupling constant
(Hz) and integration. Infrared spectra (IR) were obtained on a
Time
(h)
Yieldb
(%)
Entry R1
X
R2
3
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Br C6H5
Cl C6H5
Br 4-MeOC6H4
Br 4-EtOC6H4
Br 2,3-(MeO)2C6H3
Br 3,4-(MeO)2C6H3
29
25
20
26
39
33
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
94
97
90
97
84
90
88
90
82
92
99
80
Br 3,4-(–OCH2O–)C6H3 28
FT-IR spectrometer; absorptions were reported in cmÀ1
.
Br 3-FC6H4
Br 4-ClC6H4
Br 4-C5H11C6H4
Br n-C6H13
30
29
37
25
49
54
30
9
10
11
12
13
14
General procedure for the synthesis of 1,4-disubstituted
1,2,3-triazoles 3a–3l
3j
3k
3l
EtOOCCH2 Br C6H5
Et
Bn
I
C6H5
To a reactor containing alkyne (1.1 mmol), alkyl halide
(1.0 mmol), sodium azide (2.0 mmol) and H2O (4 mL) porous
The reactions were performed with 1 (1.0 mmol), 2 (1.1 mmol), NaN3 Cu (0.05 mmol) was added. The mixture was then sealed and
Br C6H5OCH2
3m 81
a
b
(2.0 mol), and Cu catalyst (5 mol%) in H2O at 55 1C. Isolated yields.
stirred at 55 1C until the reaction was completed as judged by
TLC. Then the reaction mixture was dissolved in ethyl acetate.
The mixture was filtered and the recovered Cu catalyst was
washed with water and methanol with no further purification
before reuse. The water layer was extracted with ethyl acetate
(3 Â 10 mL). The organic layer was washed with brine, dried
over Na2SO4 and concentrated in vacuo. The residue was
purified by flash chromatography to give the pure product.
electron densities were also studied. Alkynes not only with an
electron-donating group but also with an electron-withdrawing
group on the benzene ring all gave good isolated yields of the
expected adducts (Table 2, entries 3–10). Under the same
reaction conditions, alkyl alkyne 2j and propargyl derivative
2m were catalyzed, affording triazoles 3j and 3m in excellent
yields (Table 2, entries 11 and 14).
1-Benzyl-4-phenyl-1H-1,2,3-triazole (3a)
Moreover, we attempted recycling of porous copper; the
1
reuse investigation was performed in the model click reaction M.p. 122–124 1C (lit.9 122–124 1C); H NMR (500 MHz, CDCl3)
of benzyl bromide, sodium azide and phenylacetylene with d 7.83–7.81 (m, 2H), 7.68 (s, 1H), 7.43–7.38 (m, 5H), 7.34–7.31
5 mol% of a porous copper catalyst for 29 h. After the completion (m, 3H), 5.59 (s, 2H).
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1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (3b)
1-Benzyl-4-(4-chlorophenyl)-1H-1,2,3-triazole (3h)12
M.p. 138–140 1C (lit.10 143–144 1C); 1H NMR (500 MHz, CDCl3) M.p. 130–132 1C; 1H NMR (500 MHz, CDCl3) d 7.75 (d, J =
d 7.74 (d, J = 8.7 Hz, 2H), 7.59 (s, 1H), 7.41–7.38 (m, 3H), 8.6 Hz, 2H), 7.66 (s, 1H), 7.42–7.38 (m, 5H), 7.33 (d, J = 8.6 Hz, 2H),
7.34–7.32 (m, 2H), 6.95 (d, J = 8.7 Hz, 2H), 5.58 (s, 2H), 3.85 5.60 (s, 2H).
(s, 3H).
1-Benzyl-4-(4-pentylphenyl)-1H-1,2,3-triazole (3i)
1-Benzyl-4-(4-ethoxyphenyl)-1H-1,2,3-triazole (3c)
White solid, M.p. 139–140 1C; 1H NMR (500 MHz, CDCl3) d 7.72
1
White solid, M.p. 92–94 1C; H NMR (500 MHz, CDCl3) d 7.70
(d, J = 8.1 Hz, 2H), 7.62 (s, 1H), 7.39–7.35 (m, 3H), 7.30–7.29
(d, J = 8.9 Hz, 2H), 7.58 (s, 1H), 7.43–7.36 (m, 3H), 7.33–7.32
(m, 2H), 6.93 (d, J = 8.9 Hz, 2H), 5.58 (s, 2H), 4.07 (q, J = 7.0 Hz,
2H), 1.43 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 159.08, 148.16, 134.78, 129.17, 128.79, 128.09, 127.07,
123.07, 118.67, 114.83, 63.54, 54.27, 14.82; IR (KBr, cmÀ1):
3446.07, 3088.43 1618.74, 1502.85, 1452.96, 1251.06, 1176.28,
1116.37, 1046.27, 921.80, 815.85, 717.24. HRMS (ESI) calcd for
(m, 2H), 7.21 (d, J = 8.1 Hz, 2H), 5.56 (s, 2H), 2.60 (t, J = 7.6 Hz, 2H),
1.63–1.60 (m, 2H), 1.34–1.30 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 143.33, 143.12, 134.78, 129.12,
128.84, 128.73, 128.02, 127.91, 125.63, 119.15, 54.20, 35.69,
31.44, 31.03, 22.51, 14.00; IR (KBr, cmÀ1): 3447.27, 3090.57,
2924.43, 1637.17, 1495.09, 1455.23, 1436.61, 1414.22, 1345.62,
1220.42, 1047.93, 977.40, 817.38, 716.63. HRMS (ESI) calcd for
17H17N3O: 280.1450 (M + H)+, found 280.1421.
C
20H23N3: 306.1970 (M + H)+, found 306.1943.
C
1-Benzyl-4-(2,3-dimethoxyphenyl)-1H-1,2,3-triazole (3d)
1-Benzyl-4-hexyl-1H-1,2,3-triazole (3j)
1
M.p. 52 1C (lit.13 51–53 1C); 1H NMR (500 MHz, CDCl3)
d 7.40–7.35 (m, 3H), 7.25–7.27 (m, 2H), 7.19 (s, 1H), 5.50
(s, 2H), 2.69 (t, J = 7.7 Hz, 2H), 1.68–1.62 (m, 2H), 1.36–1.27
(m, 6H), 0.88 (t, J = 6.9 Hz, 3H).
White solid, M.p. 89–90 1C; H NMR (500 MHz, CDCl3) d 8.01
(s, 1H), 7.88 (dd, J = 8.0, 1.4 Hz, 1H), 7.40–7.35 (m, 3H),
7.32–7.30 (m, 2H), 7.16 (t, J = 8.0 Hz, 1H), 6.90 (dd, J = 8.0,
1.4 Hz, 1H), 5.61 (s, 2H), 3.89 (s, 3H), 3.75 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 152.93, 145.75, 143.50, 135.00, 129.04,
128.59, 127.84, 124.72, 124.50, 122.95, 119.63, 111.98, 59.71,
55.86, 54.05; IR (KBr, cmÀ1): 3444.01, 3166.52, 2988.13, 1583.30,
1584.73, 1342.74, 1269.69, 1231.95, 1102.12, 1044.88, 997.70,
842.93, 790.41, 722.18, 669.84. HRMS (ESI) calcd for C17H17N3O2:
296.1399 (M + H)+, found 296.1368.
Ethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetate (3k)
M.p. 92–93 1C (lit.11 80–81 1C); 1H NMR (500 MHz, CDCl3) d 7.93
(s, 1H), 7.88–7.86 (m, 2H), 7.46–7.43 (m, 2H), 7.38–7.35 (m, 1H),
5.22 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).
1-Ethyl-4-phenyl-1H-1,2,3-triazole (3l)
1-Benzyl-4-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole (3e)
M.p. 53–55 1C (lit.14 59–61 1C); 1H NMR (500 MHz, CDCl3)
d 7.86–7.84 (m, 2H), 7.78 (s, 1H), 7.46–7.43 (m, 2H), 7.36–7.33
(m, 1H), 4.48 (q, J = 7.4 Hz, 2H), 1.62 (t, J = 7.4 Hz, 3H).
White solid, M.p. 118–122 1C; 1H NMR (500 MHz, CDCl3) d 7.61
(s, 1H), 7.48 (s, 1H), 7.41–7.38 (m, 3H), 7.35–7.30 (m, 2H), 7.25
(d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.59 (s, 2H), 3.96
(s, 3H), 3.91 (s, 3H); 13C NMR (125 MHz, CDCl3) d 149.40,
149.19, 148.21, 134.80, 129.17, 128.79, 128.06, 123.66, 118.85,
118.20, 111.43, 109.09, 56.04, 55.99, 54.26; IR (KBr, cmÀ1):
3442.17, 2992.97, 1636.46, 1508.22, 1440.17, 1365.58, 1263.19,
1238.00, 1172.33, 1143.77, 1025.90, 861.00, 816.48, 718.42.
HRMS (ESI) calcd for C17H17N3O2: 296.1399 (M + H)+, found
296.1387.
1-Benzyl-4-(phenoxymethyl)-1H-1,2,3-triazole (3m)
M.p. 120–121 1C (lit.15 119–121 1C); 1H NMR (500 MHz, CDCl3)
d 7.55 (s, 1H), 7.41–7.37 (m, 3H), 7.31–7.28 (m, 4H), 7.00–6.97
(m, 3H), 5.54 (s, 2H), 5.20 (s, 2H).
Notes and references
4-(Benzo[d][1,3]dioxol-5-yl)-1-benzyl-1H-1,2,3-triazole (3f)
1 (a) C. W. Tornoe, C. Christensen and M. Meldal, J. Org.
Chem., 2002, 67, 3057; (b) V. V. Rostovtsev, L. G. Green,
V. V. Fokin and K. B. Sharpless, Angew. Chem., Int. Ed., 2002,
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White solid, M.p. 145–146 1C; 1H NMR (500 MHz, CDCl3) d 7.57
(s, 1H), 7.41–7.39 (m, 3H), 7.34–7.32 (m, 3H), 7.29 (d, J = 1.7 Hz,
1H), 6.85 (d, J = 8.0 Hz, 1H), 6.00 (s, 2H), 5.58 (s, 2H); 13C NMR
(125 MHz, CDCl3) d 148.23, 147.34, 134.48, 128.99, 128.62,
127.91, 124.57, 119.25, 118.72, 108.50, 106.25, 101.07, 54.26;
IR (KBr, cmÀ1): 3452.83, 3144.33, 2909.83, 1636.65, 1488.03,
1452.29, 1384.16, 1283.31, 1239.78, 1037.85, 694.15. HRMS
(ESI) calcd for C16H13N3O2: 280.1086 (M + H)+, found 280.1057.
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d 7.68 (s, 1H), 7.58–7.53 (m, 2H), 7.44–7.32 (m, 6H), 7.04–7.00
(m, 1H), 5.60 (s, 2H).
c
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c
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