Unusual Cu(I)-catalyzed 1,3-dipolar cycloaddition of acetylenic amides: Formation of bistriazoles

Article abstract of DOI:10.1016/j.tetlet.2012.01.069

C-carbamoyl-1,2,3-triazoles have recently attracted much interest due to their potent biological activity. While synthesizing C-carbamoyl-1,2,3-triazoles by the copper(I)-catalyzed 1,3-dipolar cycloaddition of organic azides 1 and acetylenic amides 2, we

Full text of DOI:10.1016/j.tetlet.2012.01.069

Tetrahedron Letters 53 (2012) 1606–1609
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Tetrahedron Letters
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Unusual Cu(I)-catalyzed 1,3-dipolar cycloaddition of acetylenic amides:
formation of bistriazoles
⇑
Mihyun Kwon, Yujin Jang, Sunyoung Yoon, Dongsik Yang, Heung Bae Jeon
Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
C-carbamoyl-1,2,3-triazoles have recently attracted much interest due to their potent biological activity.
While synthesizing C-carbamoyl-1,2,3-triazoles by the copper(I)-catalyzed 1,3-dipolar cycloaddition of
organic azides 1 and acetylenic amides 2, we found that the expected 1,2,3-triazole products 3 were
obtained as the only products in excellent yields when CuSO4 and sodium ascorbate were used as the
Cu(I)-catalyst. Surprisingly, the unexpected bistriazole products 4 were one of the major products
obtained along with the 1,2,3-triazoles 3 when using a direct Cu(I)-catalyst such as CuI or CuBr.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 28 November 2011
Revised 16 January 2012
Accepted 18 January 2012
Available online 28 January 2012
Keywords:
C-carbamoyl-1,2,3-triazole
Bistriazole
Cu(I)-catalyzed 1,3-dipolar cycloaddition
Acetylenic amide
The copper(I)-catalyzed 1,3-dipolar cycloaddition of organic
azides with alkynes, a click reaction, is one of the most attractive
methods for ring formation because of its high efficiency.1–4 The
synthesis of 1,2,3-triazoles using this cycloaddition has become
increasingly important due to the efficient bond formation
between diverse building blocks for chemical synthesis,5 bioconju-
gation,6 materials and surface science,7 combinatorial chemistry,8
and medicinal chemistry.9 In particular, a number of compounds
containing C-carbamoyl-1,2,3-triazoles have recently been shown
to possess a broad spectrum of biological activity.10 Even simple
C-carbamoyl-1,2,3-triazole compounds have shown antiaggregat-
ing and antithrombotic activities.11
Recently, we reported the convenient and efficient synthesis of
C-carbamoyl-1,2,3-triazoles from alkyl bromides by a one-pot
sequential addition using microwave irradiation.12 In connection
with other projects, we synthesized C-carbamoyl-1,2,3-triazoles
using a 1,3-dipolar cycloaddition between alkyl azides 1 and acety-
lenic amides 2 with CuI as the catalyst and diisopropylethylamine
(DIPEA) as the ligand at room temperature, which is one of the most
popular Cu(I)-catalyst systems for this cycloaddition. Surprisingly,
we obtained the expected 1,2,3-triazole 3 and the corresponding
bistriazole 4 in an almost equal ratio. Sharpless and co-workers
have previously observed minor amounts of bistriazole side
products, but have not reported the characterization of these
compounds.3 However, we observed significant amounts of the
bistriazoles 4, often as one of the major products, when acetylenic
amides 2 were reacted with alkyl azides 1 using direct Cu(I)-cata-
lysts such as CuI or CuBr. As far as we know, only a few Letters have
reported the synthesis and characterization of bistriazoles13–17
since the initial report by Burgess and Angell.18 Herein, we report
that the direct Cu(I)-catalyzed 1,3-dipolar cycloaddition of acety-
lenic amides affords the corresponding bistriazoles 4 as one of the
major products under the usual reaction conditions with catalytic
CuI (Eq. 1).
R3
N
N
N
N
R1
O
R1
N
N
N
R2
N
CuI(cat.)
DIPEA
DMF, rt
O
R2
R2
R1N3
+
R2
O
N
R3
N
R1
N
N
R3
O
R3
N
4
1
2
3
ð1Þ
Initially, we expected the 1,3-dipolar cycloaddition of benzyl
azide (1a) and N-phenylacetylenic amide (2a) to provide the corre-
sponding 1,2,3-triazole 3a in a high yield when treated with CuI
(0.1 equiv) and DIPEA (2 equiv) in N,N-dimethylformamide (DMF)
at room temperature. Surprisingly, the reaction afforded the
corresponding bistriazole 4a in a 58% yield as the major product.
The expected 1,2,3-triazole 3a was obtained in only a 33% yield
(Table 1, entry 1). Intrigued by this result, the reaction was carried
out in different organic solvents. When solvents such as dimethyl-
acetamide (DMA, entry 2), CH3CN (entry 3), MeOH (entry 4),
methyl formamide (entry 5), dimethyl sulfoxide (DMSO, entry 6),
and acetone (entry 7) were used, the 1,2,3-triazole 3a was obtained
as a major product with the bistriazole 4a as a minor product.
⇑
Corresponding author. Tel.: +82 2 940 5583; fax: +82 2 911 8584.
E-mail address: hbj@kw.ac.kr (H.B. Jeon).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.069

M. Kwon et al. / Tetrahedron Letters 53 (2012) 1606–1609
1607
Table 1
Cycloaddition between azide 1a and acetylenic amide 2a using CuI in various solvents
N
N
N
N
Ph
Ph
H
N
N
CuI(0.1 eq.)
O
N
N
O
Ph
H
N
DIPEA(2 eq.)
Ph
+
N
H
Ph
O
Ph
N3
Ph
Solvent
12 h, RT
N
H
O
Ph
1a
N
4a
N
2a
3a
Entry
Solvent
Yielda (%)
3a
4a
1
2
3
4
5
6
7
8
9
DMF
DMA
MeCN
MeOH
Methyl formate
DMSO
Acetone
THF
Toluene
33
54
52
64
75
58
73
95
95
58
37
27
28
17
31
20
Trace
Trace
a
Isolated yields.
Table 2
Cycloaddition between azide 1a and acetylenic amide 2a using various Cu(I)-catalysts
N
N
N
H
Ph
Ph
N
Catalyst(0.1 eq.)
N
N
N
O
O
Ph
DIPEA(2 eq.)
H
N
Ph
+
Ph
O
Ph
N3
1a
N
H
Ph
DMF
12 h, RT
N
H
N
O
Ph
N
4a
N
2a
3a
Entry
Catalyst
Yielda (%)
3a
4a
1
2
3
CuI
33
42
43
43
95
58
49
48
46
—
CuBr
CuCl
CuCN
CuSO4
4
5b
a
Isolated yields.
b
Reaction was carried out with CuSO4 (0.1 equiv) and Na ascorbate (0.25 equiv) in H2O/t-BuOH (2/1) for 12 h.
However, the use of THF (entry 8) and toluene (entry 9) as solvents
gave the 1,2,3-triazole 3a in a 95% yield with only a trace of the
bistriazole 4a.
1,2,3-triazole 3b exclusively in a 95% yield (entry 2). When acety-
lenic amide 2c derived from a secondary amine, piperidine, was re-
acted with the azide 1a in the presence of CuI, the reaction
provided bistriazole 4c as a major product in a 72% yield and
1,2,3-triazole 3c as a minor product in a 22% yield. The same reac-
tion in the presence of CuSO4 furnished only 1,2,3-triazole 3c in a
94% yield (entry 3). Further reactions with 3-phenylpropyl azide 1b
and ethyl azidoacetate 1c with the acetylenic amides 2a, 2b, and 2c
using CuI (Method A) also afforded a mixture of the corresponding
1,2,3-triazoles 3d–3i and bistriazoles 4d–4i as major products in
similar ratios. However, the same reactions using CuSO4 (Method
B) gave only the 1,2,3-triazoles 3d–3i in excellent yields as ex-
pected (entries 4–9). Although the reason for different results be-
Next, we carried out the experiments with different Cu(I) cata-
lysts (0.1 equiv), such as CuBr (Table 2, entry 2), CuCl (entry 3), and
CuCN (entry 4), in DMF. The reactions afforded the 1,2,3-triazole 3a
and bistriazole 4a in an almost equal ratio. However, when the
reaction was performed with CuSO4 (0.1 equiv) and sodium ascor-
bate (0.25 equiv) in H2O/t-BuOH (entry 5), which is one of the most
common reaction conditions for Cu(I)-catalyzed 1,3-dipolar cyc-
loadditions, 1,2,3-triazole 3a was obtained as the major product
in a 95% yield while no bistriazole 4a was observed.
Based on these interesting results, we investigated the general-
ity of this unusual Cu(I)-catalyzed 1,3-dipolar cycloaddition to
form the bistriazole from acetylenic amides using a direct Cu(I)-
catalyst, such as CuI (Table 3). A variety of organic azides and
acetylenic amides were treated with CuI (0.1 equiv) and DIPEA
(2 equiv) in DMF at room temperature (Method A).19 To compare
the results with a different copper catalyst, we also performed
the Cu(I)-catalyzed 1,3-dipolar cycloaddition with CuSO4
(0.1 equiv) and sodium ascorbate (0.25 equiv) in H2O/t-BuOH (2/
1) at room temperature with the same substrates (Method B).
The reaction of benzyl azide (1a) and N-benzylacetylenic amide
(2b) with CuI as the catalyst afforded a mixture of the correspond-
ing 1,2,3-triazole 3b and bistriazole 4b in 54% and 42% yields,
respectively. The same reaction with CuSO4 as the catalyst gave
tween method
A and B was not elucidated exactly, it is
considered that direct Cu(I)-catalysts, in particular CuI, promote
an oxidative coupling reaction to afford bistriazoles 4, and the ba-
sic reaction condition is also important to produce bistriazoles 4,
which is supported by the experiments as shown in Scheme 1.
According to the previously reported procedures,13,18 benzyl azide
(1a) and N-phenylacetylenic amide (2a) were treated with CuI in
the presence of Na2CO3 or NaOH as the base. The reactions afforded
the corresponding bistriazole 4a in 73% and 21% yields,
respectively.
As mentioned in a previous report,18 we also observed that the
core of the bistriazole molecule is chiral. Figure 1 shows a molec-
ular representation from a single-crystal X-ray analysis of bistriaz-

1608
M. Kwon et al. / Tetrahedron Letters 53 (2012) 1606–1609
Table 3
Synthesis of 1,2,3-triazole 3 and bistriazole 4 using CuI or CuSO4 on acetylenic amide 2
R3
N
N
N
N
N
R1
O
R1
N
O
N
N
R2
N
R2
R2
Method A
or
Method B
R1N3
+
N
R2
O
R3
R3
N
R1
R3
O
N
4
N
2
1
3
Method A: CuI(0.1 eq.), DIPEA(2 eq.), DMF, 12 h, RT
Method B: CuSO4(0.1 eq.), Na ascorbate(0.25 eq.), H2O/t-BuOH(2/1), 12 h, RT
Entry
Azide 1
Acetylenic amide 2
Method
Product yield (%)a
3
4
O
3a
33
95
4a
58
—
Ph
Ph
Ph
N3
A:
B:
Ph
N
1a
1a
1
2
H
2a
O
3b
54
95
4b
42
—
N3
N3
A:
B:
N
H
2b
Ph
Ph
Ph
O
3c
22
94
4c
72
—
A:
B:
1a
N
3
2c
O
3d
37
96
4d
52
—
Ph
Ph
Ph
N3
N3
N3
A:
B:
Ph
1b
1b
1b
N
H
4
5
2a
O
3e
57
95
4e
41
—
A:
B:
N
H
2b
O
3f
47
94
4f
46
—
A:
B:
N
6
2c
O
O
O
O
3g
49
95
4g
45
—
N3
N3
N3
A:
B:
Ph
O
1c
N
H
7
8
2a
O
3h
64
96
4h
34
—
A:
B:
O
1c
N
H
2b
O
3i
37
96
4i
53
—
A:
B:
O
1c
N
9
2c
a
Isolated yields.
On the contrary, when methyl propiolate (5) and propiolic acid
(7), which are derivatives of acetylenic amide, were reacted with
benzyl azide (1a) using CuI as the catalyst under the same reaction
conditions, only the corresponding 1,2,3-triazoles 6 and 8 were
produced in excellent yields (Scheme 2). This result clearly indi-
cates that the bistriazole can be obtained as one of the major prod-
ucts only when acetylenic amide is reacted with alkyl azide,
although the reason remains unclear.
In conclusion, we have found that acetylenic amides 2 react
with alkyl azide 1 using direct Cu(I)-catalyst, especially CuI, in
Cu(I)-catalyzed 1,3-dipolar cycloaddition to form the correspond-
ing bistriazoles 4 as one of the major products along with the ex-
pected 1,2,3-triazoles 3. However, we also observed that the
expected 1,2,3-triazoles 3 were provided as the only major product
in excellent yields when the same substrates were treated with
CuSO4 as the catalyst with sodium ascorbate.
CuI(0.1 eq.)
MeCN/2M Na2CO3
3a (19%) + 4a (73%)
O
18 h, RT
Ph
+
N
H
Ph
N3
CuI(0.1 eq.)
NaOH, MeOH
-35 °C, 4A MS
1a
2a
3a (69%) + 4a (21%)
Scheme 1. Cu-catalyzed cycloaddition with other bases.
ole 4b, which was performed to confirm the structure. When con-
sidering the AB-quartet pattern observed for the benzylic protons
in the 1H NMR spectrum of compound 4b,20 it becomes clear that
the rotation around the C–C bond connecting the two rings is re-
stricted because it is extremely sterically hindered.

M. Kwon et al. / Tetrahedron Letters 53 (2012) 1606–1609
1609
Figure 1. X-ray structure of bistriazole 4b.
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Ph
Ph
N
CuI(0.1 eq.)
N
N
O
DIPEA(2 eq.)
OCH3
+
+
Ph
Ph
N3
1a
OCH3
DMF
12 h, RT
O
5
6 (95%)
N
CuI(0.1 eq.)
DIPEA(2 eq.)
N
N
O
OH
N3
1a
OH
DMF
12 h, RT
O
7
8 (94%)
Scheme 2. Cu-catalyzed cycloaddition of methyl propiolate (5) and propiolic acid
(7) using CuI.
Acknowledgements
We are grateful for the support from Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Technology
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(No. 2010-0021923) and
University for this work.
a research grant of Kwangwoon
Supplementary data
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Supplementary data associated with this article can be found, in
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19. General Procedure for copper-catalyzed cycloaddition using CuI: To a solution
of alkyl azide 1 (1.1 mmol) and acetylenic amide 2 (1.0 mmol) in DMF (3 mL)
was added CuI (0.1 mmol) and DIPEA (2.0 mmol). The resulting solution was
stirred for 12 h at room temperature and then concentrated in vacuo. The
residue was subjected to column chromatography with EtOAc/CH2Cl2/hexanes
(1:2:3) as eluent to afford bistriazole 4 and 1,2,3-triazole 3 as white solids.
20. See Supplementary data.