Chemoselective preparation of disymmetric bistriazoles from bisalkynes

Article abstract of DOI:10.1016/j.tetlet.2010.11.141

Best of both worlds, molecules bearing two alkyne groups, activated and unactivated, can selectively react on the activated one in a copper-free version of Huisgen's reaction to form a first triazole ring, with a good selectivity toward the 1,4-isomer, wh

Full text of DOI:10.1016/j.tetlet.2010.11.141

Tetrahedron Letters 52 (2011) 658–660
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemoselective preparation of disymmetric bistriazoles from bisalkynes
Hichem Elamari a,b, Faouzi Meganem b, Jean Herscovici a, Christian Girard a,
⇑
a Unité de Pharmacologie Chimique, Génétique et Imagerie, UMR8151 CNRS—U1022 INSERM, Chimie ParisTech (Ecole Nationale Supérieure de Chimie de Paris),
11, rue Pierre et Marie Curie, 75005 Paris, France
b Laboratoire de Chimie Organique & Applications, Faculté des Sciences de Bizerte, 7021 Jarzouna, Bizerte, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
Best of both worlds, molecules bearing two alkyne groups, activated and unactivated, can selectively
react on the activated one in a copper-free version of Huisgen’s reaction to form a first triazole ring, with
a good selectivity toward the 1,4-isomer, which is solely isolated by a simple trituration procedure. The
other alkyne function is then submitted to the selective reaction using a polymer-supported copper(I)
catalyst to form a second triazole ring. This gave access to disymmetric bistriazoles without the need
of protection using simple, easy, and fast procedures.
Received 30 September 2010
Revised 22 November 2010
Accepted 26 November 2010
Available online 2 December 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Huisgen’s reaction
Click chemistry
Activation
Alkyne
Azide
1. Introduction
onto the resulting triazolaldehyde before the formation of the
other triazole.
Huisgen’s [3+2] thermal cycloaddition between organic azides
and alkynes, especially in it’s copper(I)-catalyzed variation, has be-
come a powerful tool for heterocycles construction; namely disub-
stituted 1,2,3-triazoles.1,2 This reaction is perfectly meeting the
requirements of the ‘click-chemistry’ concept by both its efficiency
and wide scope.3 Furthermore, the use of copper(I) catalysts not
only increased the reaction kinetics, making it possible at lower
temperatures, but also its selectivity giving rise only to the 1,4-
substituted isomer (Fig. 1).4
2. Results and discussion
For this study, molecules incorporating both an activated and
unactivated terminal alkyne were needed. We decided to study
amides of propiolic acid substituted by a distal unactivated termi-
nal alkyne on the N-substituent. The first molecule tested was N-
propargylpropiolamide (1a) as depicted in Figure 2.
We found out that the alkyne bared by the amide carbonyl was
exclusively reacting when 1a was mixed with organic azides 2a–d
under solvent- and catalyst-free conditions at room temperature
(Table 1). The resulting mono-triazoles 3a–d were obtained in
good yields (80–86%) as mixtures of 1,4- and 1,5-isomers, with a
selectivity toward the 1,4 one (1,4/1,5 = ca. 80:20).
During the course of our work on Huisgen’s reaction,5 we ob-
served an increased reactivity of some electron-withdrawing bear-
ing alkynes compared to unactivated ones, and this in the absence
of solvent, heating, or copper catalysis.6 Alkynes do not usually
spontaneously react with azides in solution, with the exception
of strained ones, as it was exemplified in in vivo click-chemistry
using cyclooctynes and their a
-gem-difluorinated analogs.7
We decided to explore and take advantage of this increased
reactivity in order to access bistriazole bearing molecules from bis-
alkyne ones. The synthesis of some 1,10-disubstituted-4,40-bistriaz-
oles has been reported using sequential approaches starting from
mono- or di-silylated butadiynes, deprotection after a first cop-
per-catalyzed Huisgen’s reaction, followed by another one or in a
one-pot fashion.8 A similar approach was proposed from propargyl
alcohol, followed by oxidation and Seyferth–Gilbert homologation
R
N
N
N
R'
R'
R
N
R
Huisgen
Huisgen
Cu(I)
1,4
+
N
N
R'
R
N
N
N
N
1,4
N
R'
N
1,5
⇑
Corresponding author. Tel.: +33 144 276 748; fax: +33 153 101 292.
E-mail address: christian-girard@chimie-paristech.fr (C. Girard).
Figure 1. Huisgen’s reaction between azides and alkynes: original thermal (1,4/1,5-
isomers) and copper(I)-catalyzed (1,4-isomer) conditions.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.141

H. Elamari et al. / Tetrahedron Letters 52 (2011) 658–660
659
1. R1N3 (2)
acetone, 65ºC
O
O
O
N
H
N
1 N
N
H
N
H
1. R1N3 (2)
R
N
2. EtOH
trituration
R1
N
N
N
neat
1,5-3
O
1b: meta
1c: para
from 1b: 1,4-7a-c
from 1c: 1,4-8a-c
N
H
O
2. EtOH
trituration
N
H
O
1a
R2N3 (2)
N
1 N
R
N
N
H
R2
N
A-21.CuI
CH2Cl2
R1 N
N
N
N
N
1,4-3
R2N3 (2)
O
from 7: 9a-i
from 8: 10a-i
N
H
R2
N
N
1 N
N
A-21.CuI
CH2Cl2
2a: AcO(CH2)2N3, 2b: PhCH2N3, 2c: EtO2CCH2N3
R
N
N
4-6
Figure 3. Sequential Huisgen’s reactions of propiolamides of meta- (1b) and para-
ethynylaniline (1c) with azides 2.
2a: AcO(CH2)2N3, 2b: PhCH2N3, 2c: EtO2CCH2N3
2d: PhCH2O2CCH2N3, 2e: HO(CH2)2N3
Table 2
Figure 2. Sequential chemoselective preparation of bistriazoles from N-propargyl-
propiolamide (1a) and azides 2.
Results for the preparation of bistriazoles 9 and 10 from bisalkynes 1b and 1c
1
R1N3
—
7/8 [%]
(1,4/1,5)
1,5-7/8b [%] 1,4-7/8c [%] R2N3
9/10 [%]
a
a
Fortunately, a simple trituration with ethanol gave pure 1,4-3 as
solids after filtration (52–61%), while the solvent contained mainly
the 1,5-isomer (14–23%), together with a small amount of the 1,4
one (1,4/1,5 = ca. 25:75). In this first step, only the ethyl ester of
azidoacetic acid (2c) failed to give a solid compound upon tritur-
ation (3c, 82% yield, 1,4/1,5 = 74:26). The use of its benzyl ester
analog 2d, however, circumvented the problem by giving a crystal-
line derivative.
Pure 1,4-3a, 3b, and 3d were then used for a second Huisgen’s
reaction, using this time a copper(I)-supported catalyst; Amberlyst
A-21ꢀCuI,5a in order to access bistriazoles 4–6 (Fig. 2, Table 1).
Mono-triazoles 3 all reacted equally well with azides 2a–e under
these conditions, at room temperature, giving the corresponding
bistriazoles 4–6/a–e in a high average yield of 95%.9
(1,4/1,5)
—
—
1b 2a
2b
7a, 78 (80:20) 12 (32:68)
7b, 85 (78:22) 11 (21:79)
7c, 74 (81:19) 15 (29:71)
8a, 87 (83:17) 10 (24:76)
8b, 61 (77:23) 9 (37:63)
8c, 76 (85:15) 12 (34:66)
61
2a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
9a, 93
9b, 97
9c, 98
9d, 99
9e, 96
9f, 92
9g, 91
9h, 96
9i, 99
10a, 96
10b, 95
10c, 99
10d, 92
10e, 96
10f, 97
10g, 94
10h, 98
10i, 96
67
56
72
48
58
2c
1c 2a
2b
2c
The compounds were isolated as highly crystalline products
after a simple filtration to remove the catalyst and evaporation of
the reaction solvent. Furthermore, as for all copper(I)-catalyzed
Huisgen’s reactions, only the 1,4-isomer of the newly formed tria-
zole was observed.
a
b
c
For structures of 1b, 1c and 2a–c, see Figure 3.
Contained in EtOH trituration solution.
Solid isolated after EtOH trituration.
In order to make a first evaluation of the scope of this method,
we decided to test the sequential procedure on propiolamides de-
rived from meta- (1b) and para-ethynylaniline (1c), as illustrated in
Figure 3. The bisalkynes 1b and 1c are very light solids that were
not well in contact with the liquid azides 2a–c. The procedure
has thus to be changed to run it using some solvent. Acetone was
selected, but only a few percent conversions were observed at
room temperature for an over-night reaction. The reaction mixture
was then heated to reflux and, to our surprise, only the activated
alkyne on 1b and 1c reacted once again. This gave access to the first
triazole nucleus, 7 and 8, respectively, as isomeric mixtures (1,4/
1,5 = ca. 80:20) with good yields between 61% and 87% (Table 2).
Trituration of the crude in ethyl alcohol gave access to the pure
crystalline 1,4-isomers of 7 and 8 in 48–72% yield and to the 1,5/
1,4-isomers mix in solution.
Each of the six mono-triazole 1,4-7a–c and 8a–c were then
reacted with the same azides (2a–c) using the above mentioned
solid-phase catalyst for Husigen’s reaction. The corresponding
bistriazoles 9a–i and 10a–i were isolated in very good yields in
each case, as their 1,4-isomers once again (average yield of 96%).9
Table 1
Results of preparation of bistriazoles 4–6 from 1a
R1N3
—
3 [%]
(1,4/1,5)
1,5-3b [%]
(1,4/1,5)
1,4-3c [%]
—
R2N3
—
4 [%]
a
a
2a
3a, 86 (84:16)
17 (26:74)
61
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
—
2a
2b
2c
2d
2e
4a, 99
4b, 96
4c, 95
4d, 98
4e, 92
5a, 96
5b, 95
5c, 94
5d, 92
5e, 93
—
6a, 95
6b, 93
6c, 89
6d, 97
6e, 94
2b
3b, 84 (79:21)
23 (24:76)
52
2c
2d
3c, 82 (74:26)
3d, 80 (82:18)
—
—
60
14 (18:82)
3. Conclusion
a
b
c
We presented in this Letter a new approach for the synthesis of
disymmetric bistriazoles starting from unprotected bisalkynes
using Huisgen’s reaction. The reactivity difference between what
For structures of 1a and 2a–e, see Figure 2.
Contained in EtOH trituration solution.
Solid isolated after EtOH trituration.

660
H. Elamari et al. / Tetrahedron Letters 52 (2011) 658–660
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was called an activated and unactivated alkyne, gave the opportu-
nity to introduce chemoselectively a first triazole ring on the acti-
vated part of the molecule, in a catalyst-free way, with or without a
solvent. The resulting mono-triazoles, obtained in good yields
mainly as their 1,4-disubsituted isomers, were easily obtained pure
after a simple trituration and filtration. The products were then
submitted to a copper(I)-catalyzed Huisgen’s reaction to form the
second triazole ring on the unactivated alkyne, with exclusive 1,4
selectivity and in high yields. Further work on the application of
this selective method is in progress and will be reported in due
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Acknowledgments
This work is a part of the international thesis of H. Elamari—
Université P. & M. Curie/Université du 7 Novembre à Carthage. It
was supported by fellowships from Ministry of Education of Tuni-
sia and UPCG; and Grants CNRS (UMR 8151) and INSERM(U 1022).
We thank Dr. Marie-Nöelle Rager for NMR experiments and helpful
discussions.
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9. Typical procedures. General procedure for solvent- and catalyst-free Huisgen’s
reaction on the activated alkyne: To bisalkyne 1a (0.5 mmol) was added azide 2
(0.55 mmol). The mixture was stirred 18 h at room temperature. The crude
was triturated in EtOH (8 mL) and filtrated to obtain the solid 1,4-3. For the
reactions conducted in solution, alkyne 1b–c was dissolved in acetone (4 mL),
azide 2 added and the solution heated at reflux (65 °C) for 24 h. The same
work-up was made after evaporation of acetone. General procedure for copper-
catalyzed Huisgen’s reaction on the unactivated alkyne: Mono-triazole 3 (7 or 8)
(0.2 mmol) was dissolved in CH2Cl2 (2 mL) and the azide 2 (0.22 mmol) and
Amberlyst A-21ꢀCuI (12 mg, 8 mol %) were sequentially added. The resulting
suspension was stirred at room temperature until completion of the reaction
(16–48 h), before being filtered and the polymer washed with CH2Cl2
(2 ꢁ 1 mL). Evaporation of the solvent gave the corresponding bistriazole 4–6
(9 or 10).
Supplementary data
Supplementary data associated with (complete experimental
procedures, analyses and NMR spectra) this article can be found,
in the online version, at doi:10.1016/j.tetlet.2010.11.141.
References and notes
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