On the reactivity of activated alkynes in copper and solvent-free Huisgens reaction

Article abstract of DOI:10.1016/j.tetasy.2010.06.013

Terminal alkynes substituted by a carbonyl-type electron-withdrawing group have been found to undergo Huisgens cycloaddition with azides at room temperature in a solvent-free manner; without a need of either heating or catalysis. Metallic salts, other tha

Full text of DOI:10.1016/j.tetasy.2010.06.013

Tetrahedron: Asymmetry 21 (2010) 1179–1183
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
On the reactivity of activated alkynes in copper and solvent-free
Huisgen’s reaction
Hichem Elamari a,b, Ibtissem Jlalia a,b, Charlotte Louet a, Jean Herscovici a, Faouzi Meganem b,
Christian Girard a,
*
a Pharmacologie Chimique, Génétique & Imagerie—UMR 8151 CNRS/U 1022 INSERM/IFR 2769, Ecole Nationale Supérieure de Chimie de Paris (Chimie ParisTech),
11 rue Pierre et Marie Curie, 75005 Paris, France
b Laboratoire de Chimie Organique & Applications, Faculté des Sciences de Bizerte, Université du 7 Novembre à Carthage, 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:
Terminal alkynes substituted by a carbonyl-type electron-withdrawing group have been found to
undergo Huisgen’s cycloaddition with azides at room temperature in a solvent-free manner; without a
need of either heating or catalysis. Metallic salts, other than the copper ones also efficiently catalyzed
the reactions. The yields were good and the products isolated mainly as their 1,4-disubstituted isomer.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 2 March 2010
Accepted 10 June 2010
Available online 3 July 2010
Dedicated to Henri B. Kagan; a great
scientist and human being, a mentor
and a friend
1. Introduction
2. Results and discussion
Since the introduction of the click-chemistry concept, several
reactions were used to quickly and efficiently construct molecular
architectures.1 One of the most studied reactions in this field is the
copper(I)-catalyzed version of Huisgen’s 1,3-dipolar cycloaddition
between organic alkynes and azides (copper-catalyzed alkyne–
azide cycloaddition or CuAAC) leading to the 1,2,3-triazole ring
(Scheme 1).2
This catalyzed variation of the initial Huisgen’s reaction pre-
sents various advantages: the reaction usually do not need heat-
ing to proceed, the cycloaddition is relatively fast and,
furthermore, it gives selectively the corresponding 1,4-disubsti-
tuted triazole isomer over the 1,5-one. Several conditions to con-
duct the CuAAC have been proposed since it’s discovery ranging
from in situ generation of copper(I) species from redox systems
starting with cupric salts or copper itself3 to the use of soluble
cuprous salt or complexes,4 as well as metallic copper (wire,
nanoparticles, and clusters)5 and copper(I)-supported catalysts
(polymers, minerals, and ionic liquids).6 In the field of supported
catalysts, we explored the use of polymer and clay supports, in
solution and solvent-free conditions.7 During our work on Wyo-
ming montmorillonite (Wy), and its use as a Huisgen catalyst
in solution after adsorption of copper(I) iodide (WyÁCuI), we ob-
served interesting reactivity behaviors that were worthy to be
explored in more detail.
In order to ascertain the catalytic activity of WyÁCuI, the modi-
fied clay was first tested in the [3+2] reaction between phenylacet-
ylene 1a, methyl propiolate 1b, and benzyl azide 2a as models
(Table 1). Blanks were also run using the reference sodium-rich
Wyoming montmorillonite (S-Wy-2) and the same after complete
sodium-exchange procedure (Wy-Na).
When the reaction was run in solution in methylene chloride,
phenylacetylene 1a did not react with benzyl azide 2a in the pres-
ence of S-Wy-2 and Wy-Na or in the absence of clay. When WyÁCuI
was used, the corresponding triazole 1a2a as its sole 1,4-isomer
was quantitatively formed. The same was true when the solvent-
free procedure was applied; only WyÁCuI gave rise to the complete
transformation into the 1,4-isomer of triazole 1a2a.
In the case of methyl propiolate 1b, the results were quite dif-
ferent and interesting. In solution, the formation of the triazole
1b2a was observed even when S-Wy-2 and Wy-Na were used in
50% and 39% conversion, respectively, and in a 9 to 1 ratio in favor
of the 1,4-isomer.
Even when no additives were present, the conversion reached
10% in the same ratio. Furthermore, WyÁCuI gave a complete con-
version and selectivity for the corresponding 1b2a. The results
were even better when the reaction was run under solvent-free
conditions. Yields in the presence of S-Wy-2 and Wy-Na increased
up to 80%, and without additive to 50%, all in a 9:1 ratio. Once
again, WyÁCuI selectively and quantitatively gave the 1,4-isomer
of 1b2a.
From these results, WyÁCuI was working equally well with phe-
nyl 1a or methoxycarbonyl 1b-substituted acetylene, both under
solution and solvent-free conditions.
* Corresponding author. Tel.: +33 1 44 27 67 48; fax: +33 1 53 10 12 92.
E-mail address: christian-girard@chimie-paristech.fr (C. Girard).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.013

1180
H. Elamari et al. / Tetrahedron: Asymmetry 21 (2010) 1179–1183
R1
Huisgen Cu(I) catalyzed:
R1
R2 N3
+
H
N
N
R2
CuX / base or
N
CuX2 / ascorbic acid or
copper, nanoparticles or
zeolite or polymer supported
copper (I), etc.
1,4 isomer
R1
R1
Huisgen (thermal)
N
N
N
N
R2
R2
N
N
1,5
1,4
Scheme 1. Huisgen’s reaction between azides and alkynes: original thermal (1,4/1,5-isomers) and copper(I)-catalyzed (1,4-isomer) conditions.
For phenylacetylene 1a, this substance did not react in solution
added since no copper was detected below 50 ppm by elemental
analysis. Furthermore, phenylacetylene 1a failed to react in the
presence of these clays, but reacted perfectly in the presence of
WyÁCuI (4.57% copper by elemental analysis). When looking at nat-
ural sodium-rich Wyoming montmorillonite composition: (Ca0.12-
K0.05Na0.32)[Al3.01Fe0.41Mg0.54Mn0.01Ti0.02][Al0.02Si7.98]O20(OH)4, the
major metallic oxides constituents, excluding Na and Ca, are Si
(62.9%), Al (19.6%) Fe (3.7%), and Mg (3.0%). The hypothesis that
metals included in the clays can have a catalytic influence was
made.
Thus for the study, the behavior in Huisgen’s reaction of alkynes
bearing a carbonyl (ester, carboxylic acid, ketone, and amide) was
studied under solvent-free conditions on three azides, in the pres-
ence or absence of additives representative of the main metals
found in the clays (SiO2, Al2O3, FeCl3, and MgCl2), as well as copper
salts (CuCl2 and CuI) and WyÁCuI; the results are presented in
Table 2.
When phenylacetylene 1a was mixed with benzyl azide 2a,
ethyl azidoacetate 2b, or 2-acetoxyethyl azide 2c, no reaction
was observed in the absence or presence of SiO2, Al2O3, FeCl3,
MgCl2, and CuCl2. The use of CuI gave the 1,4-isomer of triazoles
1a2a and 1a2b in very good yields, but surprisingly not the forma-
tion of 1a2c. With WyÁCuI, all three triazoles were formed in high
yields and complete selectivity.
or neat, in the presence or absence of clays (S-Wy-2 and Wy-Na).
Methyl propiolate 1b reacted without additive in solution or neat
in conversion reaching 10% and 50%, respectively. The addition of
both clays (S-Wy-2 and Wy-Na) increased the yields to 50% in solu-
tion and 80% in the solvent-free conditions.
These results led to three observations: (1) The best results
were obtained using the solvent-free approach, (2) acetylene bear-
ing an electron-withdrawing group such as an ester 1b was react-
ing while the one substituted with a stabilizing group such as
phenyl 1a did not; and (3) the presence of clays (S-Wy-2 and
Wy-Na) seemed to have a catalytic effect on the reaction under
both conditions.
In order to gain a better understanding of the phenomena tak-
ing place here, we decided to conduct a more complete study based
on these initial results. Dilution in these cases seems to have dele-
terious effect on the conversion, thus solvent-free conditions were
selected.
Since the presence of an electron-withdrawing group, such as
an ester, seemed to be in part responsible for the reactivity, alkynes
bearing a carbonyl-type substituent were chosen.
The presence of copper traces in the clays S-Wy-2 and Wy-Na
cannot be accounted for the reactions happening when they were
The reaction of methyl propiolate 1b with the three azides 2a,
2b, and 2c, without additives, gave fair yields (50–75%) of the cor-
responding triazoles 1b2a, 1b2b, and 1b2c with 1,4- to 1,5-iso-
meric ratios of 90 to 10. By adding SiO2, Al2O3, FeCl3, MgCl2, and
CuCl2 to the reagents, the yields were better (80–99%) with mainly
ratios of 90 to 10, with only a few being in the range of 85:15 to
80:20. The addition of either CuI or WyÁCuI gave a complete trans-
formation into the awaited triazoles as their 1,4-isomer.
Table 1
Results of the reaction of alkynes 1a and 1b with the azide 2a to form triazoles 1a2a
and 1a2b in the presence of Wya
R1
H
R1
M
1,4-isomer
1a, R1 = Ph
N
N
1b, R1 = CO2Me
Bn
N
Wy•M (8 mol %)
Propiolic acid 1c was found to be quite reactive under solvent-
free conditions, with or without additives. It was also the sole com-
pound in this study to exhibit a noticeable exothermal reaction
with the azides. Reactions with 2a–c, without additives, gave a
complete conversion into the triazoles 1c2a, 1c2b, and 1c2c with
good selectivities for their 1,4-isomer (91:9 and 87:13). The addi-
tion of SiO2, Al2O3, FeCl3, MgCl2, and CuCl2 did not really improve
the results. Nevertheless, the triazoles were still formed in very
good yields (83–99%), once again mainly at the 90:10 level for
the selectivities, with some in the range of 95:5 and 85:15. The
use of CuI and WyÁCuI also gave high yields for the three triazoles.
However, the selectivity for the 1,4-isomer was not complete in
these cases and ranged between 92:8 and 95:5. The same selectiv-
ities were obtained even by changing the order of addition of the
reagents in this specific case (CuI and WyÁCuI).
+
and/or
CH2Cl2, R.T.
or
solvent-free
R1
Bn N3
1,5-isomer
2a
N
N
Bn
N
1a2a, R1 = Ph; 1b2a, R1 = CO2Me
b
Solvent
Triazole
S-Wy-2b
%, ratioc
Wy-Nab
%, ratioc
WyÁCuIb
—
%, ratioc
%, ratioc
CH2Cl2
None
1a2a
1b2a
1a2a
1b2a
0
0
99, 10:0
99, 10:0
99, 10:0
99, 10:0
0
50, 9:1
0
80, 10:1
39, 9:1
0
80, 9:1
10, 9:1
0
50, 9:1
a
On a 0.5 mmol scale: 1 equiv alkyne, 1.1 equiv azide, 2 mL solvent (0.25 M),
18 h reaction time, room temperature.
b
The next molecule tested was acetylacetylene (butyn-3-one,
1d). The reactions of the ketone 1d with the azides without addi-
tives gave good yields between 77% and 83% in triazoles 1d2a,
55 mg of clay (WyÁCuI = 8 mol % Cu). —: without additives.
c
Estimated by 1H NMR: conversion %, ratio 1,4: 1,5 isomers. All compounds gave
correct IR, 1H, 13C NMR, and LC–MS analyses.

H. Elamari et al. / Tetrahedron: Asymmetry 21 (2010) 1179–1183
1181
Table 2
Reactivity of alkynes 1n toward azides 2n under solvent-free conditions in the presence of additivesa
R1
R1
solvent-free
additive
R1
R2 N3
and/or
+
H
N
N
N
N
R.T., 18 h
R2
1,4-isomer
N
R2
1,5-isomer
N
1n
2n
1n2n
Ph
N3
EtO2C
N3
N3
Azide
AcO
Alkyne
Ph
b
Additive
2a %, ratio
2b %, ratiob
2c %, ratiob
1a2a
0
0
1a2b
0
0
1a2c
0
0
None
SiO2
1a
Al2O3
FeCl3
MgCl2
CuCl2
CuI
0
0
0
0
0
0
0
0
0
0
0
0
94, 100:0
99, 100:0
99, 100:0
90, 100:0
0, 100:0
99, 100:0
WyÁCuI
1b2a
50, 89:11
1b2b
72, 90:10
1b2c
76, 90:10
CO2CH3
None
SiO2
1b
84, 86:14
82, 90:10
83, 88:12
81, 90:10
84, 94:6
99, 80:20
99, 90:10
—
96, 90:10
99, 87:13
99, 100:0
99, 100:0
98, 86:14
99, 90:10
99, 90:10
99, 90:10
99, 90:10
99, 100:0
99, 100:0
Al2O3
FeCl3
MgCl2
CuCl2
CuI
94, 100:0
99, 100:0
WyÁCuI
CO2H
1c2a
99, 91:9
1c2b
99, 87:13
1c2c
99, 91:9
None
SiO2
1c
99, 93:7
94, 91:9
99, 96:4
94, 94:6
93, 92:8
99, 94:6
90, 93:7
99, 91:9
99, 94:6
83, 88:12
99, 92:8
99, 82:18
99, 95:5
99, 92:8
92, 89:11
92, 87:13
91, 92:8
97, 93:7
84, 83:17
99, 92:8
99, 93:7
Al2O3
FeCl3
MgCl2
CuCl2
CuI
WyÁCuI
1d2a
77, 94:6
1d2b
77, 94:6
1d2c
83, 94:6
COCH3
CONHPh
CH(OEt)2
None
SiO2
1d
65, 93:7
77, 92:8
81, 96:4
79, 92:8
84, 95:5
83, 94:6
99, 100:0
81, 94:6
80, 93:7
—
80, 92:8
83, 88:12
82, 95:5
99, 100:0
79, 91:9
78, 93:7
—
78, 93:7
84, 94:6
87, 96:4
99, 100:0
Al2O3
FeCl3
MgCl2
CuCl2
CuI
WyÁCuI
1e2a
53, 85:15
1e2b
57, 81:19
1e2c
65, 86:14
None
SiO2
1e
96, 90:10
92, 91:9
81, 92:8
79, 88:12
82, 95:5
96, 100:0
98, 100:0
99, 87:13
54, 78:22
83, 88:12
58, 78:22
83, 88:12
94, 100:0
91, 100:0
91, 78:22
94, 76:24
87, 88:12
82, 90:10
90, 92:8
Al2O3
FeCl3
MgCl2
CuCl2
CuI
86, 100:0
90, 100:0
WyÁCuI
1f2a
3, 72:28
3, 76:24
1f2b
2, 83:17
3, 71:29
1f2c
2, 83:17
4, 85:15
None
SiO2
1f
WyÁCuI
80, 100:0
93, 100:0
96, 100:0
a
On a 0.5 mmol scale: 1 equiv alkyne, 1.1 equiv azide, 8 mol % additive, 18 h reaction time, room temperature.
Estimated by 1H NMR: conversion %, ratio 1,4: 1,5 isomers. —: product chelating Fe, no interpretable results available. All compounds gave correct mp, IR, 1H, 13C NMR,
b
and LC–MS analyses.
1d2b, and 1d2c with a 94:6 selectivity. The addition of the above-
mentioned additives gave global conversions in the same range
(65–84%) with similar selectivites than without additives (88:12
to 96:4). The addition of CuI gave similar yields (84%), but some
of the 1,5-isomer was observed in this case (95:5 ratio). However,
WyÁCuI gave complete conversion and selectivity for the 1,4-iso-
mers of triazoles 1d2a–c.
Finally the reactivity of an amide derivative, namely N-phenyl-
propiolamide 1e, was evaluated.8 The reaction with azides 2a–c
without additives gave moderate yields (53–65%) with lower selec-
tivities between 81:19 and 86:14 in favor of the 1,4-isomer of
1e2a–c. The addition of SiO2, Al2O3, FeCl3, MgCl2, and CuCl2 im-
proved the conversion in most cases (79–99%) with some excep-
tions (54–58%), but selectivities were variable being for each one

1182
H. Elamari et al. / Tetrahedron: Asymmetry 21 (2010) 1179–1183
R
N
Bn N3
2a
N
A-21•CuI
N
HN
HN
HN
CH2Cl2
O
O
O
neat
R-N3
(2b, 2c, 2d)
N
N
N
N
Bn
Bn
N
N
1g
1g2a
1g2a2b, 94%, R = CH2CO2Et
1g2a2c, 96%, R = (CH2)2OAc
1g2a2d, 99%, R = (CH2)3OH
52% (1,4) after
recrystallization
Scheme 2. Examples of sequential Huisgen reactions using a bisalkyne containing activated/unactivated alkynes to access dissymmetric bistriazoles.
third lower, equal, and higher than without additives. The use of
copper(I) catalyst also gave in these cases a complete selectivity
for the 1,4-isomers in good yields both for CuI (86–96%) and for
WyÁCuI (90–98%).
corresponding bistriazoles were obtained solely as their 1,4-iso-
mers in 94% 1g2a2b, 96% 1g2a2c, and 99% 1g2a2d isolated yields.
3. Conclusion
When looking at the results as a function of the additive used,
the average yields observed for Huisgen’s cycloaddition without
them (76%) was increased in each case. The order was found to
be SiO2 (90%), CuCl2 (89%), Al2O3/FeCl3 (87%), and MgCl2 (85%).
Copper(I) catalysis gave higher average yields of 93% (CuI) and
97% (WyÁCuI). It thus seemed that the use of such additives has a
positive effect on the global yields in this series.
The effect seemed to be related to the presence of the additives
since reactions conducted in their absence are giving lower conver-
sions. The effect cannot be attributed to the nature of the vial in
which the reaction was performed, since the use of borosilicate
or plastic test tubes did not change the outcome of the reactions.
If a catalytic effect is taking place here, it is possible that it can
be due to either the adsorption or the dispersion of the reagents
onto the additives, or by chelation. Complexation of the metals
by the carbonyl groups, or hydrogen bonding with silanols in the
case of silica, may increase the reactivity of the alkynes by a Lewis
acid-type catalysis. As an added proof, the reactions of propiolalde-
hyde diethyl acetal 1f (Table 2), where the carbonyl is masked, only
gave 2–4% conversion in the absence of additives or in the presence
of silica, which gave the best results in this study. Once again the
use of WyÁCuI gave the triazoles 1f2a–c in good yields 80–96%
and complete 1,4-selectivity.
In the case of CuCl2, using these conditions, it did not seem that
copper(I) was formed during its use since phenylacetylene 1a did
not react. The formation of the copper(I) species has been reported
while using copper(II) salts (CuCl2, Cu(OAc)2, and CuSO4) in water
or alcoholic solvents.9 The cuprous species generation was a result
of either oxidation of the alcohol or some Glaser coupling initially
taking place. Phenylacetylene 1a was found to react with azides in
these cases. However, the formation of some copper(I) cannot be
completely ruled out while using the activated alkynes 1b–e, even
if a total 1,4-selectivity was not observed here.
In order to demonstrate the utility of this study, we present
herein a first example of application using a bisalkyne incorporat-
ing both an activated and an unactivated acetylene (Scheme 2). N-
Propargylpropiolamide (1g)10 was first mixed with benzyl azide
(2a) in solvent- and additive-free conditions to form 1g2a in 84%
yield and in a 76:24 ratio in favor of the 1,4-isomer.11 The reaction
occurred only on the activated alkyne, no reaction was observed on
the propargyl side-chain. Recrystallization in ethanol gave 52% of
the pure 1,4-isomer of 1g2a which was used in the following steps.
The triazole–alkyne 1g2a was then reacted with ethyl azidoac-
etate 2b, 2-acetoxyethyl azide 2c, and 3-azidopropanol 2d. Since
1g2a is a solid, we decided to use a solution approach for this sec-
ond step using our previously described polymer-supported cop-
per(I) catalyst (Amberlyst A-21ÁCuI) in methylene chloride. The
Herein we have presented our findings on the behavior of car-
bonyl-bearing acetylenes in Huisgen’s cycloaddition under sol-
vent-free conditions. It was determined that these ‘activated’
alkynes reacted spontaneously with azides in moderate to good
yields. The addition of natural clays, or the use of metallic salts
and oxides, was found to have an effect on the efficiency of the
reaction of activated acetylenes. A catalytic influence was proposed
based on the presence of a carbonyl group on these alkynes and its
complexation with metals. Unactivated alkynes do not react under
these conditions, in the presence or absence of the additives. This
gave us the opportunity to present a first example of a sequential
and regioselective formation of dissymmetric bistriazoles based
on reactivity differences for a molecule bearing both activated
and unactivated acetylenes. This approach has many applications
to selectively introduce triazole rings to functionalize or form
derivatives and analogues of chiral natural products, such as amino
acids or peptides. Results on this subject will be presented in due
course.
Acknowledgments
Fellowship for an international thesis from Tunisia for H.E. is
greatly acknowledged. This work has been conducted under the
grants CNRS 8151 and INSERM 1022.
References
1. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 113,
2056–2075. Angew. Chem., Int. Ed. 2001, 40, 2004–2021; (b) Kolb, H. C.;
Sharpless, K. B. Drug Discovery Today 2003, 8, 1128–1137; (c) Moses, J. E.;
Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249–1262.
2. (a) Huisgen, R. Angew. Chem., Int. Ed. 1963, 75, 604–637; Huisgen, R. Angew.
Chem., Int. Ed. Engl. 1963, 2, 565–598; (b) Tornøe, C. W.; Meldal, M. In 17th
American Peptides Symposium Proceedings Book Peptides: The Wave of the Future.
In Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions on Solid phase; Lebl, M.;
Houghten, R.A., Eds; American Peptide Society and Kluwer Academic: San
Diego, 2001; pp. 263–264.; (c) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057–3064; (d) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 114, 2708–2711. Angew. Chem., Int.
Ed. 2002, 41, 2596–2599; (e) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H.
Eur. J. Org. Chem. 2006, 51–68; (f) Wu, P.; Fokin, V. V. Aldrichim. Acta 2007, 40,
7–17; (g) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952–3015.
3. (a) Beckmann, H. S. G.; Wittmann, V. Org. Lett. 2007, 9, 1–4; (b) Tao, C.-Z.; Cui,
X.; Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2007, 48, 3525–3529; (c)
Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9, 1809–1811.
4. (a) Zhang, X.; Hsung, R. P.; Li, H. Chem. Commun. 2007, 2420–2422; (b)
Bertrand, P.; Gesson, J.-P. J. Org. Chem. 2007, 72, 3596–3599; (c) Peddibhotla, S.;
Dang, Y.; Liu, J. O.; Romo, D. J. Am. Chem. Soc. 2007, 129, 12222–12231.
5. (a) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E. Org. Lett. 2004,
6, 4223–4225; (b) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210–216; (c) David,

H. Elamari et al. / Tetrahedron: Asymmetry 21 (2010) 1179–1183
1183
O.; Maisonneuve, S.; Xie, J. Tetrahedron Lett. 2007, 48, 6527–6530; (d) Durán
Pachón, L.; van Maarseveen, J. H.; Rothenberg, G. Adv. Synth. Catal. 2005, 347,
811–815; (e) Molteni, G.; Bianchi, C. L.; Marinoni, G.; Santo, N.; Ponti, A. New J.
Chem. 2006, 30, 1137–1139.
10. Prepared according to: Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Nishiyama, H.;
Itoh, K. Org. Biomol. Chem. 2004, 2, 1287–1294.
11. Typical procedure: CAUTION—Organic azides are potentially explosive and
should be handled with care.
6. (a) Lipshutz, B. H.; Taft, B. R. Angew. Chem., Int. Ed. 2006, 45, 8235–8238; (b)
Chassaing, S.; Kumarraja, M.; Sani Souna Sido, A.; Pale, P.; Sommer, J. Org. Lett.
2007, 9, 883–886; (c) Chan, T. R.; Fokin, V. V. QSAR Comb. Sci. 2007, 26, 1274–
1279; (d) Sharghi, H.; Khalifeh, R.; Doroodmand, M. M. Adv. Synth. Catal. 2009,
351, 207–218; (e) Bonami, L.; Van Camp, W.; Van Rijckegem, D.; Du Prez, F. E.
Macromol. Rapid Commun. 2009, 30, 34–38; (f) Chtchigrovsky, M.; Primo, A.;
Gonzalez, P.; Molvinger, K.; Robitzer, M.; Quignard, F.; Taran, F. Angew. Chem.,
Int. Ed. 2009, 48, 5916–5920; (g) Hagiwara, H.; Sasaki, H.; Hoshi, T.; Suzuki, T.
Synlett 2009, 643–647; (h) Raut, D.; Wankhede, K.; Vaidya, V.; Bhilare, S.;
Darwatkar, N.; Deorukhkar, A.; Trivedi, G.; Salunkhe, M. Catal. Commun. 2009,
10, 1240–1243.
7. (a) Girard, C.; Önen, E.; Aufort, M.; Beauvière, S.; Samson, E.; Herscovici, J. Org.
Lett. 2006, 8, 1689–1692; (b) Aufort, M.; Herscovici, J.; Bouhours, P.; Moreau,
N.; Girard, C. Bioorg. Med. Chem. Lett. 2008, 18, 1195–1198; (c) Jlalia, I.; Elamari,
H.; Meganem, F.; Herscovici, J.; Girard, C. Tetrahedron Lett. 2008, 49, 6756–
6758; (d) Jlalia, I.; Meganem, F.; Herscovici, J.; Girard, C. Molecules 2009, 14,
528–539.
1-Benzyl-N-(prop-2-yn-1-yl)-1H-1,2,3-triazole-4-carboxamide 1g2a: Benzyl
azide (2a, 73 mg, 0.55 mmol) was added to N-propargylpropiolamide 1g
(54 mg, 0.5 mmol) in a small test tube. The mixture was stirred for 18 h at
room temperature. The product 1g2a was obtained as a 76:24 mixture of 1,4-
and 1,5-isomers (101 mg, 84%). After crystallization from EtOH, the pure 1,4-
isomer was isolated as
M = 240.26 g molÀ1, mp: 204 °C; FTIR:
1213, 1057 and 715 cmÀ1 1H NMR (DMSO-d6, 300 MHz): d 3.10 (t, J = 2.4 Hz,
a
pale yellow solid (64 mg, 52%).
C13H12N4O,
m
3015, 2944, 1741, 1654, 1568, 1362,
.
1H), 4.01 (dd, J = 5.9, 2.4 Hz, 2H), 5.67 (s, 2H), 7.34–7.43 (m, 5H), 8.71 (s, 1H),
and 8.98 (t, J = 5.9 Hz, 1H) ppm; 13C NMR (DMSO-d6, 75.5 MHz): d 27.9, 53.1,
72.6, 81.2, 126.8, 128.0, 128.3, 128.8, 135.6, 142.5 and 159.4 ppm; LC–MS:
ELSD pur. 98%; Rt = 4.19 min; m/z: 241 ([M+H]+) and 263 ([M+Na]+).
Ethyl 2-(4-{[(1-benzyl-1H-1,2,3-triazol-4-yl)formamido]methyl}-1H-1,2,3-triazol-
1-yl)acetate 1g2a2b: The triazole–alkyne 1g2a (48 mg, 0,2 mmol) was
dissolved in CH2Cl2 (2 mL), and ethyl azidoacetate 2b (28 mg, 0.55 mmol)
and Amberlyst A-21ÁCuI (13 mg, 8 mol %) were sequentially added. The
suspension was stirred at room temperature for 18 h, before being filtered
and the polymer was washed with CH2Cl2 (2 Â 1 mL). After evaporation,
product 1g2a2b was obtained as a yellow solid (174 mg, 94%). C17H19N7O3,
8. Prepared according to: Payne, R. J.; Peyrot, F.; Kerbarh, O.; Abell, A. D.; Abell, C.
Chem. Med. Chem. 2007, 2, 1015–1029.
9. For some copper(II) and/or copper(I) catalysis in these cases, see: (a) Rajender
Reddy, K.; Rajgopal, K.; Lakshmi Kantam, M. Synlett 2006, 957–959; (b) Song,
Y.-J.; Yoo, C.; Hong, J.-T.; Kim, S.-J.; Son, S. U.; Jang, H.-Y. Bull. Korean Chem. Soc.
2008, 29, 1561–1564; (c) Brotherton, W. S.; Michaels, H. A.; Simmons, J. T.;
Clark, R. J.; Dalal, N. S.; Zhu, L. Org. Lett. 2009, 11, 4954–4957; (d) Fiandanese,
V.; Bottalico, D.; Marchese, G.; Punzi, A.; Capuzzolo, F. Tetrahedron 2009, 65,
10573–10580; (e) Namitharan, K.; Kumarraja, M.; Pitchumani, K. Chem. Eur. J.
2009, 15, 2755–2758.
M = 369.15 g molÀ1, mp: 217 °C; FTIR:
m 3341, 3278, 3011, 1745, 1650, 1568,
1362, 1222, 831 and 731 cmÀ1 1H NMR (DMSO-d6, 300 MHz): d 1.22 (t,
.
J = 7.1 Hz, 3H), 4.17 (q, J = 7.1 Hz, 2H), 4.51 (dd, J = 5.8, 0.3 Hz, 2H), 5.35 (s, 2H),
5.67 (s, 2H), 7.35–7.40 (m, 5H), 7.95 (s, 1H), 8.69 (s, 1H), and 9.10 (t, J = 4.9 Hz,
1H) ppm; 13C NMR (DMSO-d6, 75.5 MHz): d 14.2, 34.4, 50.5, 53.3, 61.7, 126.9,
128.2, 128.5, 129.1, 135.9, 159.8 and 167.5 ppm; LC–MS: ELSD pur. 99%;
Rt = 4.33 min; m/z: 370 ([M+H]+) and 392 ([M+Na]+).