Efficient synthesis of 1,4-disubstituted 1,2,3-triazoles in ionic liquid/water system

Article abstract of DOI:10.1016/j.tetlet.2006.01.004

A copper(I) catalyst in a mixture of the ionic liquid [bmim][BF ₄] and water, can effect three-component reaction of halides, sodium azide and alkynes to form 1,4-disubstituted 1,2,3-triazoles in good to high yields. The method is efficient and environmentally friendly.

Full text of DOI:10.1016/j.tetlet.2006.01.004

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1545–1549
Efficient synthesis of 1,4-disubstituted 1,2,3-triazoles in ionic
liquid/water system
Ya-Bin Zhao, Ze-Yi Yan and Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
Received 22 October 2005; revised 26 December 2005; accepted 4 January 2006
Available online 20 January 2006
Abstract—A copper(I) catalyst in a mixture of the ionic liquid [bmim][BF ] and water, can effect three-component reaction of
4
halides, sodium azide and alkynes to form 1,4-disubstituted 1,2,3-triazoles in good to high yields. The method is efficient and envi-
ronmentally friendly.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1
,2,3-Triazoles are important five-membered nitrogen
Room temperature ionic liquids are environmentally
benign solvents due to their unique chemical and physi-
cal properties, and have proved to be especially useful in
heterocycles, involved in a wide range of industrial
applications such as agrochemicals, corrosion inhibi-
tions, dyes, optical brighteners and biologically active
6
the case of catalytic reactions. Ionic liquid has also
1
7
agents. Earlier, the compounds are in general prepared
shown promising results, such as hydrogenations,
8
through the coupling reaction between alkynes and
azides to form a mixture of 1,4-substituted- and 1,5-
substituted-1,2,3-triazoles at high temperature.2 The
recent important investigations led to the ‘click’ chemis-
Diels–Alder reaction, enantioselective allylation reac-
tions enantioselective epoxidation of alkenes and
enantioselective ring opening of epoxides. Although
9
10
11
coupling reactions of aryl halides with sodium azide
3
12
try approach. Sequentially, the copper(I)-catalyzed
was reported, and Zhong and Guo developed a ther-
Huisgen cycloaddition reaction of azides and terminal
alkynes has emerged as a novel alternative, and received
much attention since its discovery. The methodology has
found applications in drug discovery, bioconjugations
mal 1,3-dipolar cycloaddition of alkynes to azides in
1
3
ionic liquid, however, no attempt has been made for
the use of ionic liquids in copper(I)-catalyzed Huisgen
cycloaddition process. Herein, we reported an efficient
and safe recyclable one-pot three-component reaction
in ionic liquid to form 1,4-disubstituted 1,2,3-triazoles.
Reaction of various halides, sodium azide with terminal
alkynes in [bmim][BF ]/H O afforded corresponding
4
and materials science. Exclusive regioselectivity, wide
substrate scope and mild reaction conditions have made
it the method of choice for making permanent connec-
tions by means of 1,4-disubstituted 1,2,3-triazoles. For
instance, in the last few years, the copper(I)-catalyzed
Huisgen cycloaddition reaction has been widely used
4
2
triazoles in good to excellent yields (Scheme 1).
in multi-component reactions (MCRs) to prepare
Initially, we investigated the catalytic activity of various
copper catalysts for the MCR of benzyl chloride,
5
1
,2,3-triazoles with various functional groups.
N
N
N
NaN ,[bmim][BF ]/H O
X
3
4
2
Fe
Fe
CuI, Na CO3
2
X = Cl, Br
Scheme 1.
*
0
Corresponding author. Tel.: +86 931 8912596; fax: +86 931 8912582; e-mail: liangym@lzu.edu.cn
040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.004

1546
Y.-B. Zhao et al. / Tetrahedron Letters 47 (2006) 1545–1549
a
Table 1. Evaluation of catalysts in the reaction
Table 3. Recycle of [bmim][BF
4
]/H
2
O reaction medium
b
a
Entry
Catalyst
Time (h)
Yield (%)
Entry
Cycle
Time (h)
Yield (%)
1
2
3
4
5
CuCN
CuBr
CuCl
CuI
6
6
6
4
8
72
65
45
75
63
1
2
3
4
5
0
1
2
3
4
4
3.5
4
5
4
94
91
92
93
92
CuSO
4
/Vc
a
a
All reactions were carried out using 0.5 mmol benzyl chloride,
.5 mmol phenylacetylene, 15 mol % copper salts catalyst, 0.6 mmol
Isolated yield.
0
NaN
3
and 1 mmol Na
2
CO
3
in 4 ml [bmim][BF
4
]
at room
temperature.
Isolated yield.
copper(II) catalysts such as CuBr , CuCl and CuSO
2 2 4
b
showed no catalytic effect. Although some workers
reported that copper metal could catalyze the cycloaddi-
tion in low yield, in this study, no reaction occurred in
the presence of copper(0) either copper powder or cop-
Table 2. Evaluation of various solvents for the reaction
1
4
a
per turning. Attempts to explore other metal catalysts
Entry
Solvent
Time (h)
Yield (%)
such as AgCl, AgBr, AgI and ZnCl failed. Although all
Cu(I) species showed the good catalytic properties, the
best effect was observed by using CuI (Table 1, entry 4).
2
1
2
3
4
5
6
DMSO
THF
[bmim][BF
[bmim][BF
[bmim][BF
4
4
4
4
4
30
35
75
80
94
90
4
4
4
]
]/H
]/H
O 1:4
2
O 1:4
O 1:1
We also evaluated the solvent effect in the three-compo-
nent reaction. The results evaluating the merits of vari-
ous solvents are presented in Table 2. It was shown
that ionic liquid was a type of feasible reaction medium
in Huisgen cycloaddition. In comparison with the reac-
tions in organic solvent and water, it only took 4 h in io-
nic liquids to give moderate yield. To our surprise, using
[bmim][BF ]/H O 1:1 instead of [bmim][BF ], the corre-
2
DMSO/H
2
24
a
Isolated yield.
sodium azide and phenylacetylene in ionic liquid. As
expected, the cycloaddition reaction proceeded well in
the presence of 15 mol % of copper salts (CuI, CuBr,
4
2
4
CuCl, CuCN and Vc-CuSO system) to give triazole in
sponding product was obtained in excellent yield (Table
2, entry 5). We presumed that water played a positive
role in the present system due to good water solubility
4
4
5–75% yield (Table 1, entries 1–5). But, compared to
7
5% yield in [bmim][BF ], only trace of the correspond-
4
1
5
ing product was isolated by using CuI in water. Sole
of sodium azide.
3
Table 4. Reactions of halides, alkynes and NaN to form corresponding triazoles
Entry
Alkyne
Halide
T (ꢁC)
Time (h)
Product
Yield (%)
99
N
N
N
Br
1
rt
8
8
Fe
Fe
.
N
N
N
Cl
2
3
rt
rt
97
75
Fe
Fe
N
N
N
Br
10
Fe
Fe
N
N
N
Br
4
5
rt
rt
4
4
97
94
N
N
N
Cl

Y.-B. Zhao et al. / Tetrahedron Letters 47 (2006) 1545–1549
1547
Table 4 (continued)
Entry
Alkyne
Halide
T (ꢁC)
Time (h)
5
Product
Yield (%)
N
N
N
Br
6
rt
76
N
N
N
N
N
7
8
rt
rt
5
4
90
96
Br
N
Br
N
N
N
Cl
9
rt
4
8
95
80
N
N
I
N
10
65
Fe
Fe
N
N
N
N
I
N
1
1
1
2
65
65
7
6
72
83
I
N
N
N
I
N
1
1
3
4
65
65
8
8
70
75
N
N
N
N
N
OCH
3
H
3
CO
I
N
N
NH
2
1
5
H2
N
I
75
10
72
68
N
N
NO
2
1
1
6
7
O2N
I
80
12
20
Br
100
No reaction
Having optimized the reaction conditions, the recycl-
ability of three-component reaction with copper(I)
catalysts in [bmim][BF ]/H O was examined (Table 3).
Similar high conversions were obtained, showing that
the ionic liquid remained active. Furthermore, no signi-
ficant loss of the ionic liquid was observed after five
4
2

1548
Y.-B. Zhao et al. / Tetrahedron Letters 47 (2006) 1545–1549
N
N
N
NaN , [bmim][BF ]/H O
I
3
4
2
Fe
L-Proline, CuI, Na CO
2
3
Fe
Scheme 2.
cycles, which indicated that it could be recycled effi-
ciently in this way.
References and notes
1
. Reviews on 1,2,3-triazoles, see: (a) Wamhoff, H. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 5, pp
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2. (a) L’abb e´ , G. Chem. Rev. 1969, 69, 345–363; (b) Huisgen,
R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Chapter 1; pp 1–176; (c)
Padwa, A. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, (d)
Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2001, 40, 2004; (b) Rostovtsev, V. V.;
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4. (a) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.;
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Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
Having established the recyclability and reuse of the
ionic liquid, the scope and generality of this method
was illustrated with respect to various triazoles (Table
6
4
). It is important to stress that we explored the Huisgen
1
reaction of ferrocenylacetylene because ferrocene-con-
taining heterocyclic rings were reported to be useful
materials in electrochemistry, biochemistry and material
1
6
science. Up to now, although the Cu(I) catalyzed reac-
tion of alkynes and azides have been widely reported, no
attempt was carried out to synthesize triazoles including
ferrocene segment. Herein, we were pleased to find that
ferrocenylacetylene would be compatible with azide and
1
7
copper catalyst.
In order to understand more about the effect of the cop-
per(I)-catalyzed Huisgen cycloaddition reaction in ionic
3
2
liquids, we extended our study by using halides at sp -
hybridized carbon atoms (phenyl halides). At room tem-
perature, it was failed to complete the reaction of phenyl
halides. Thus, we had to explore new reaction system
(
Scheme 2). The reaction temperature and various auxi-
1
8
liary conditions were examined. We found that the
reaction of iodobenzene, alkynes and sodium azide pro-
ceeded well in the presence of 20% L-proline at 65 ꢁC,
and gave the corresponding products in 68–83% conver-
sion (Table 4, entries 10–16). An attempt to extend the
reaction to bromobenzene was proved to be not effec-
tive. No expected product was isolated even elevating
the temperature to 100 ꢁC.
2
002, 67, 3057; (d) Wang, Z. X.; Lin, H. L. Chem.
Commun. 2003, 2450; (e) Rheingold, A. L.; Liable-Sands,
L. M.; Trofimenko, S. Angew. Chem., Int. Ed. 2000, 39,
321; (f) Trofimenko, S.; Rheingold, A. L.; Incarvito, C.
D. Angew. Chem., Int. Ed. 2003, 42, 3506.
3
5. (a) Kamijo, S.; Jin, T. N.; Huo, Z. B.; Yamamoto, Y.
Tetrahedron Lett. 2002, 43, 9707; (b) Appukkuttan, P.;
Dehaen, W.; Fokin, V. V.; Eycken, E. V. D. Org. Lett.
2
004, 6, 4223; (c) Feldman, A. K.; Colasson, B.; Fokin, V.
In conclusion, we found that the ionic liquid/H O was a
2
V. Org. Lett. 2004, 6, 3897; (d) Kamijo, S.; Jin, T.; Huo, Z.
B.; Yamamoto, Y. J. Org. Chem. 2004, 69, 2386.
6. (a) Welton, T. Chem. Rev. 1999, 2071; (b) Wasserscheid,
P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772; (c)
Sheldon, R. Chem. Commun. 2001, 2399.
good reaction medium for the one-pot synthesis of 1,4-
3
disubstituted 1,2,3-triazoles using either halides at sp -
2
hybridized carbon atoms or halides at sp -hybridized
carbon atoms in good yields. Better performance was
obtained than that of conventional reaction condition.
This procedure permits extensive recycling of the solvent
without substantial loss in activity within five times. On
the basis of the current efforts, it seems to be likely that a
number of metal catalyzed transformations could be
performed equally well or even more effectively in this
ionic liquid. Studies to determine applicability to other
catalytic reactions are currently underway in our lab.
7
. Some examples of hydrogenation using ionic liquids: (a)
Chauvin, Y.; Mussman, L.; Olivier, H. Angew. Chem., Int.
Ed. Engl. 1995, 34, 2698; (b) Suarez, P. A. Z.; Dullins, J. E.
L.; Einloft, S.; de Souza, R. F.; Dupont, J. Tetrahedron:
Asymmetry 1997, 8, 177; (c) Brown, R. A.; Pollet, P.;
McKoon, E.; Eckert, C. A.; Liotta, C. L.; Jessop, P. G. J.
Am. Chem. Soc. 2001, 123, 1254.
8
9
. Some examples of Diels–Alder reactions in ionic liquids:
(
1
a) Jaeger, D. A.; Tucker, C. E. Tetrahedron Lett. 1989, 30,
785; (b) Fischer, T.; Sethi, A.; Welton, T.; Woolf, J.
Tetrahedron Lett. 1999, 40, 793.
. McCluskey, A.; Garner, J.; Young, D. J.; Caballero, S.
Tetrahedron Lett. 2000, 41, 8147.
Acknowledgements
We thank the NSFC-20021001, NSFC-20572038 and
the ‘Hundred Scientist Program’ from the Chinese
Academy of Sciences for financial support of this work.
1
0. Song, C.-E.; Roh, E. J. Chem. Commun. 2000, 837.
11. Song, C.-E.; Oh, C. R.; Roh, E. J.; Choo, D. J. Chem.
Commun. 2000, 1743.

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1549
12. Zhu, W.; Ma, D.-W. Chem. Commun. 2004, 888.
13. Zhong, P.; Guo, S.-R. Chin. J. Chem. 2004, 22, 1183.
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Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am.
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organic extracts were washed with brine, dried over
anhydrous Na SO filtered and concentrated in vacuo.
The residual crude product was purified via silica gel. Ionic
liquid was recovered by extracting with dichloromethane
2
4
and can be reused for the same reactions. 1-Benzyl-4-
1
cyclohex-1-ene-1-H-[1,2,3]triazole:
3
H NMR (CDCl ,
6
1, 9331.
5. Liao, M.-C.; Duan, X.-H.; Liang, Y.-M. Tetrahedron Lett.
005, 46, 3469.
300 MHz, d ppm): 7.32 (s, 1H), 7.30–7.17 (m, 5H), 6.43
1
1
(t, H), 5.41 (s, 2H) 2.29 (t, 2H), 2.11 (t, 2H), 1.56–1.71 (m,
1
3
2
3
4H); C NMR (CDCl , 75 MHz, d ppm): 150.3, 135.5,
6. (a) Benito, A.; Martinez-Manez, R.; Paya, J.; Sots, J.;
129.4, 128.9, 128.3, 127.8, 125.3, 118.9, 118.8, 54.3, 26.8,
+
Tendero, M. J. L.; Sinn, E. J. Organomet. Chem. 1995,
25.7, 22.9, 22.7; MS: m/z = 239 (M ), 210, 182, 120, 91,
À1
5
1
03, 259; (b) Butler, I. R.; Roustan, J.-L. Can. J. Chem.
991, 69, 1117; (c) Liu, C.-M.; Chen, B.-H.; Liu, W.-Y.;
77. IR (KBr, cm ): 3103, 2927, 1454, 1431, 1215, 1070.
18. Procedure for the reaction of phenyl iodide: other reaction
conditions are the same as benzyl chloride, reaction could
proceed in the presence of L-proline (24 mg, 20 mol %)
Wu, X.-L.; Ma, Y.-X. J. Organomet. Chem. 2000, 598,
48.
7. Representative procedure: benzyl chloride (64 mg,
.5 mmol), phenylacetylene (52 mg, 0.5 mmol) and NaN
39 mg, 0.6 mmol) were placed in a 10 ml round-bottomed
flask. Sequentially, Na CO (106 mg, 1 mmol) and CuI
15 mol %) were added, the reaction mixture was stirred in
3
1
at 65 ꢁC. 1-(4-Methylphenyl)-4-phenyl-1-H-[1,2,3]triazole:
1
0
3
3
H NMR (CDCl , 300 MHz, d ppm): 8.16 (s, 1H), 7.91
(
(d, J = 8.1, 2H), 7.60 (d, J = 8.1, 2H), 7.48–7.45 (m, 2H),
13
2
3
3
7.39–7.31 (m, 3H), 2.43 (s, 3H); C NMR (CDCl ,
(
75 MHz, d ppm): 148.2, 138.8, 134.7, 130.3, 130.2, 128.9,
+
4
ml [bmim][BF ]/H O 1:1 at room temperature for 4 h
128.3, 125.8, 120.4, 117.6, 21.1; MS: m/z = 235 (M ), 206,
4
2
À1
and then extracted with ether (3 · 10 ml). The combined
116, 91. IR (KBr, cm ): 3124, 1520, 1230, 1044.