A new solvent system for efficient synthesis of 1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2006.05.079

The use of CH₂Cl₂ as a co-solvent with H₂O in the copper(I)-catalyzed 1,3-dipolar cycloaddition of organic azides and alkynes increased reaction rates and provided the corresponding 1,2,3-triazoles in excellent yields comp

Full text of DOI:10.1016/j.tetlet.2006.05.079

Tetrahedron Letters 47 (2006) 5105–5109
A new solvent system for efficient synthesis of 1,2,3-triazoles
Bo-Young Lee, So Ra Park, Heung Bae Jeon* and Kwan Soo Kim*
Center for Bioactive Molecular Hybrids, Department of Chemistry, Yonsei University, Seodaemun-gu
Sinchon-dong 134, Seoul 120-749, Republic of Korea
Received 28 February 2006; revised 9 May 2006; accepted 15 May 2006
Abstract—The use of CH2Cl2 as a co-solvent with H2O in the copper(I)-catalyzed 1,3-dipolar cycloaddition of organic azides and
alkynes increased reaction rates and provided the corresponding 1,2,3-triazoles in excellent yields compared to other organic co-sol-
vent systems. Moreover, we applied this discovery to prepare the functional multivalent compound in an excellent yield.
Ó 2006 Elsevier Ltd. All rights reserved.
The copper(I)-catalyzed 1,3-dipolar cycloaddition of
organic azides and alkynes1 resulting in the formation
of 1,2,3-triazoles has become an increasingly attractive
area because it is a highly efficient process in bond for-
mations among diverse building blocks for chemical
synthesis,2 bioconjugation,3 materials and surface
science,4 and combinatorial chemistry.5 In addition, a
number of compounds containing 1,2,3-triazoles have
shown a broad spectrum of biological activities such
as antibacterial,6 herbicidal, and fungicidal,7 antialler-
gic,8 and anti-HIV.9
CH2Cl2 has been employed as solvent in the ligand-med-
iated copper(I) catalyzed 1,3-dipolar cycloaddtion, it
was used for organic ligand which accelerated the reac-
tion rate, not as a co-solvent.10a Herein, we report our
successful application of CH2Cl2 as the co-solvent in
ligand-free reaction.
Initially, compound 3 was supposed to be easily synthe-
sized by treating azide 1 with the terminal alkyne 2 in
H2O/EtOH (entry 1 in Table 1). However, the reaction
did not proceed at all. Then, the reactions were carried
out in different organic co-solvents such as CH3CN
(entries 2 and 3), DMSO (entry 4), THF (entry 5), and
t-BuOH (entry 6), but they all failed. Surprisingly, the
addition of CH2Cl2 to H2O/t-BuOH mixture drove the
reaction to proceed, and the desired product 3 was iso-
lated in 60% yield in 24 h (entry 7). More surprisingly,
the reaction was completed in 2 h when it was run in
CH2Cl2/H2O as the solvent system, and gave product
3 in 96% yield (entry 8).
In general, the copper(I)-catalyzed 1,3-dipolar cyclo-
addition is known as a mild reaction that does not require
much specific precautions. It usually proceeds to com-
pletion in 6–36 h at ambient temperature in water with
a variety of organic co-solvents, such as tert-butanol,
ethanol, DMSO, THF, or CH3CN. However, it is still
of interest to develop more efficient cycloaddition meth-
ods, since reactions that involve the azides or alkynes
having the low reactivity require long reaction times
and give low yields. A few papers recently reported that
the addition of ligand, a copper(I) stabilizer, enhanced
the catalytic activity of copper(I), improved reaction
yields, and reduced reaction times.10
Next, the generality of this solvent system in the cop-
per(I)-catalyzed 1,3-dipolar cycloaddition was investi-
gated. A variety of organic azides and alkynes were
treated with CuSO4Æ5H2O (5 mol %) and sodium ascor-
bate (15 mol %) in CH2Cl2/H2O (1/1). All substrates
investigated gave 1,2,3-triazoles in excellent yields (Ta-
ble 2). In order to show the efficiency of CH2Cl2/H2O
solvent system, the same reactions were also performed
in t-BuOH/H2O (2/1), which is one of the most popular
solvent systems used for the click reaction. The reaction
of phenylacetylene (4) and benzyl azide (9) in CH2Cl2/
H2O afforded 1,2,3-triazole 16 in 97% yield after 7 h,11
whereas the same reaction in t-BuOH/H2O furnished
Interestingly, in recent days we discovered that 1,2,3-tri-
azole 3 could be successfully prepared when we used
CH2Cl2 as organic co-solvent in the ligand-free cop-
per(I) catalyzed 1,3-dipolar cycloaddtion. Although
*
Corresponding authors. Tel.: +82 2 2123 2640/7615; fax: +82 2 365
7608; e-mail addresses: hbj@yonsei.ac.kr; kwan@yonsei.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.079

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B.-Y. Lee et al. / Tetrahedron Letters 47 (2006) 5105–5109
Table 1. The copper(I)-catalyzed synthesis of 1,2,3-triazole 3 in various solvent systemsa
BzO
BzO
BzO
OBz
O
O
N
H
+
O
O
N3
O
O
2
1
BzO
OBz
O
O
BzO
BzO
N
H
N
O
O
N
O
O
N
3
Entry
CuSO4Æ5H2O (mol %)
Sodium ascorbate (mol %)
Solvent
Temperature
Time (h)
3, Yieldb (%)
1
2
3
4
5
6
7
8
5
5
25
25
30
30
30
40
15
15
H2O/EtOH (2:1)
H2O/CH3CN (2:1)
H2O/CH3CN (1:1)
H2O/DMSO/CH3CN (1:2:2)
H2O/CH3CN/THF (1:2:2)
H2O/t-BuOH (2:1)
rt
rt
rt
rt
rt
rt
rt
rt
24
24
24
24
24
24
24
2
None
None
None
None
None
None
60
10
10
10
20
5
H2O/t-BuOH/CH2Cl2 (1:2:1)
H2O/CH2Cl2 (1:1)
5
96
a Reaction condition: 1 (1 equiv), 2 (1.1 equiv), solution concentration (0.05 M).
b Isolated yields.
Table 2. Effect of the use of CH2Cl2 in the copper(I)-catalyzed 1,3-dipolar cycloaddition
Entry
Alkyne
Azide
Product
Methoda
Time (h)
Yieldb (%)
N3
1
A
B
7
24
97
83
N
N
9
N
N
4
16
N3
2
3
4
4
A
B
2
24
99
96
N
N
N
N
N
N
10
17
18
19
MeO
O2N
N3
4
4
A
B
5
24
99
92
MeO
N
N
11
12
N3
A
B
2
24
85
37
O2N
BzO
BzO
OBz
O
OBz
BzO
BzO
O
BzO
BzO
5
6
4
4
A
B
1
24
94
80
O
N
O
N3
N
N
13
20
O
O
N3
A
B
3
3
95
93
HO
N
HO
N
N
14
21

B.-Y. Lee et al. / Tetrahedron Letters 47 (2006) 5105–5109
5107
Table 2 (continued)
Entry
Alkyne
Azide
Product
Methoda
Time (h)
Yieldb (%)
O
7
9
A
B
5
24
99
93
O
5
N
N
N
22
O
O
N
N
8
9
A
B
2
24
99
98
N
N
N
6
23
N
N
N
N
N
N
N
N
9
9
A
B
12
24
98
93
N
N
N
7
24
O
O
N
N
10
11
9
A
B
1.5
24
93
89
H
H
N
N
N
N
2
25
O
O
N
H
2
13
A
B
11
24
99
98
N
HO
N
26
AcO
AcO
AcO
O
AcO
AcO
AcO
O
OAc
N
12
A
B
6
24
94
34
N
OAc
N3
8
N
15
27
a Method A: CH2Cl2/H2O (1/1), rt. Method B: t-BuOH/H2O (2/1), rt.
b Isolated yields.
16 in 83% yield after 24 h (entry 1). This result clearly
indicates that the reaction rate in CH2Cl2/H2O has
increased significantly compared to that in t-BuOH/
H2O. The click reaction of 4 with azides 10, 11, 12,
and 13 also showed the increased reaction rates in
CH2Cl2/H2O (entries 2–5), except for the reaction with
azidoacetic acid (14), which provided 21 in excellent
yields in both solvent systems (entry 6). Next, the click
reactions of azide 9 were performed with propargyl
ether 5 (entry 7), acetylenic amide 612 (entry 8), triprop-
argylamine (7) (entry 9), and propargyl amide 2 (entry
10). All reactions provided the desired 1,2,3-triazoles
22, 23, 24,10b and 25 in excellent yields. In particular,
in the case of acetylenic amide 6, which is known for
its low reactivity toward 1,3-dipolar cycloaddition with
azides,12 the click reaction gave 23 in a quantitative yield
after only 2 h. The reaction of alkyne 8 with sugar azide
15 in CH2Cl2/H2O afforded the 1,2,3-triazole 27 in 94%
yield after 6 h, whereas the reaction in t-BuOH/H2O
gave 27 in 34% yield after 24 h. Clearly, the new solvent
system, CH2Cl2/H2O, increased the yield of the forma-
tion of the 1,2,3-triazoles and reduced the reaction
times. Although the reason was not elucidated exactly,
it is considered that the high solubility of the substrates
in CH2Cl2 makes the reaction faster.
The application of the new reaction condition to synthe-
size a multivalent ligand was next explored. The initial
attempt to carry out the click reaction of azide-function-
alized sugar 13 and alkyne-functionalized trivalent core
compound 28 did not work in either CH2Cl2/H2O or t-
BuOH/H2O even after 24 h (Scheme 1), whereas the
reaction of 13 with 4 afforded the 1,2,3-triazole 20 in
excellent yield (entry 5 in Table 2). Although it was
not clear why the reaction of 13 with 28 did not work,
this was easily overcome by using azide-functionalized
sugar 29 in place of 13. The reaction proceeded success-
fully in CH2Cl2/H2O in 1 h to give the trivalent com-
pound 30 in 96% yield, whereas the reaction in
t-BuOH/H2O gave 30 in 29% yield even after 24 h.

5108
B.-Y. Lee et al. / Tetrahedron Letters 47 (2006) 5105–5109
BzO
OBz
O
.
BzO
CuSO4 5H2O (15 mol%)
BzO
Na ascorbate (45 mol%)
O
No reaction
No reaction
N3
O
H2O/CH2Cl2 (1:1), 24 h
13
+
H
N
.
CuSO4 5H2O (15 mol%)
O
O
O
O
Na ascorbate (45 mol%)
H2O/t-BuOH (1:2), 24 h
H
N
H
N
O
O
O
O
O
O
O
O
O
O
28
.
CuSO4 5H2O (15 mol%)
Na ascorbate (45 mol%)
BzO
OBz
H2O/CH2Cl2 (1:1)
O
1 h, 96%
BzO
BzO
28
+
.
CuSO4 5H2O (15 mol%)
O
O
N3
Na ascorbate (45 mol%)
H2O/t-BuOH (1:2)
24 h, 29%
O
O
29
H
O
N R
N
N
O
O
N
O
O
O
O
O
O
R =
OBz
OBz
H
N
H
N
R
R
O
BzO
OBz
O
O
30
H
N
O
O
N3
BzO
BzO
OBz
O
O
O
+
BzO
H
H
N3
O
N
N
O
N3
O
O
O
O
O
O
O
31
O
O
32
.
.
CuSO4 5H2O (15 mol%)
Na ascorbate (45 mol%)
CuSO4 5H2O (15 mol%)
Na ascorbate (45 mol%)
H2O/CH2Cl2 (1:1)
1 h, 93%
H2O/t-BuOH (1:2)
24 h, 32%
H
O
N
R
O
O
O
O
O
O
N
R =
N
H
N
H
N
OBz
OBz
N
R
R
O
BzO
OBz
O
O
33
Scheme 1.
Conversely, the reaction of the alkyne-functionalized
sugar 31 and azide-functionalized trivalent core compound
32 in CH2Cl2/H2O also afforded 33 in 93% yield after
1 h, compared to 32% yield after 24 h in t-BuOH/H2O.
system, demonstrating the synthetic application to struc-
turally complex molecules.
Acknowledgment
In conclusion, we have found that the use of CH2Cl2 as
a co-solvent with H2O in the copper(I)-catalyzed 1,3-
dipolar cycloaddition of organic azides and alkynes sig-
nificantly increases the reaction rates in comparison to
other organic co-solvent systems. This reaction condi-
tion eliminates the need of ligands and simplifies the
reaction protocol. Moreover, we have shown that this
solvent system is generally applicable to cycloaddition
reactions involving various azides and alkynes, and tol-
erates a number of different functional groups. Finally,
the synthesis of the multivalent compounds 30 and 33
was done efficiently in excellent yields using this solvent
This work was supported by a Grant from the Korea
Science and Engineering Foundation through Center
for Bioactive Molecular Hybrids (CBMH).
References and notes
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phenylacetylene (4, 100 mg, 0.75 mmol) and benzyl azide
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(0.7 mL) were added CuSO4Æ5H2O (9.3 mg, 0.04 mmol)
and sodium ascorbate (22 mg, 0.11 mmol). The resulting
solution was stirred for 7 h at room temperature. The
reaction mixture was diluted with CH2Cl2 (5 mL) and
H2O (5 mL). The organic layer was separated, dried over
MgSO4, and concentrated. The residue was purified by
flash column chromatography (hexane/EtOAc, 2:1) to give
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