A highly active and reusable copper(I)-tren catalyst for the "click" 1,3-dipolar cycloaddition of azides and alkynes

Article abstract of DOI:10.1039/b716306a

The copper(I) complex [Cu(C18₆tren)]Br 1 (C18₆tren = tris(2-dioctadecylaminoethyl)amine) which exhibits a good stability towards aerobic conditions is a versatile, highly reactive and recyclable catalyst for the Huisgen cycloaddition

Full text of DOI:10.1039/b716306a

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A highly active and reusable copper(I)-tren catalyst for the ‘‘click’’
1,3-dipolar cycloaddition of azides and alkynes{
Nicolas Candelon, Dominique Laste´coue`res, Abdou Khadri Diallo, Jaime Ruiz Aranzaes, Didier Astruc and
Jean-Marc Vincent*
Received (in Cambridge. UK) 23rd October 2007, Accepted 26th November 2007
First published as an Advance Article on the web 10th December 2007
DOI: 10.1039/b716306a
recovery under an active form by simple filtration in air. We now
report that 1 is a versatile, highly reactive and recyclable catalyst
for the Huisgen cycloaddition of azides with terminal or internal
alkynes and is a useful catalyst for the preparation of ‘‘click’’
dendrimers.
The copper(I) complex [Cu(C186tren)]Br 1 (C186tren = tris(2-
dioctadecylaminoethyl)amine) which exhibits a good stability
towards aerobic conditions is a versatile, highly reactive and
recyclable catalyst for the Huisgen cycloaddition of azides with
terminal or internal alkynes and is a useful catalyst for the
preparation of ‘‘click’’ dendrimers.
Since the independent discovery by the groups of Sharpless1 and
Meldal2 that Cu(I) was an efficient and regiospecific catalyst for
the Huisgen 1,3-dipolar cycloaddition of azides and terminal
alkynes,3 this transformation has emerged as one of the most
powerful ‘‘click’’ reactions.4,5 Recently, Finn and coworkers
reported that tris(2-benzimidazolylmethyl)amines were powerful
accelerating ligands for the CuSO4/sodium ascorbate catalytic
system.6 Some very active,7 or recyclable8 copper(I) catalytic
systems which do not require a sacrificial reductant have been
reported as well. However, the high reactivity of Cu(I) complexes
towards dioxygen, in particular those bearing polyamino ligands,
often make them very difficult to handle thus limiting their
practical interest. Cu(I) complexes typically react with dioxygen to
form unstable m-peroxo-dicopper(II) intermediates evolving into
highly reactive bis-m-oxo-dicopper(III) which then decomposes
irreversibly through oxidation processes.9 By employing more
crowded tetradentate tripodal ligands such as Me6tren,10 or a
tris(tetramethylguanidino)tren (TMG3tren),11 the stability of the
1 : 1 [Cu(L)O2]+ Cu(II)-superoxo adducts can be greatly improved
by lowering or inhibiting the formation of the [Cu2(L)2O2]2+
peroxo dimers. In the case of the very crowded TMG3tren ligand,
reversible binding of O2 was demonstrated with no detectable
decomposition of the copper(I) complex.11a
Unlike 1, the 1,4-disubstituted-1,2,3-triazoles products are polar
products. Therefore we decided to run the reactions in solvents of
low polarity (toluene or n-octane) to promote the selective
precipitation of the products. The results reported in Table 1 for
a range of azides 2 and acetylenes 3 show that in most cases the
reactions can be carried out efficiently in these solvents using
0.05 mol% of catalyst affording the corresponding 1,4-disubsti-
tuted-1,2,3-triazoles 4 in good to excellent yields.{
The reactions are run in air-equilibrated solutions under mild
conditions (60 uC) showing the good stability of 1. All the products
reported in Table 1 were isolated with analytical purity via simple
filtration under aerobic conditions after cooling the reaction
mixture at 218 uC for 2 h. The choice of the solvent is governed
by the nature of the product. For the less polar triazoles, the
n-octane is favoured to ensure a good precipitation. The low
polar catalyst 1 which is fully soluble in toluene or n-octane
stays in the filtrate which can be reloaded with the substrates for a
second reaction. The catalyst was reused two times, affording the
triazoles with no decrease in the yield (Entries 4–6). This
exemplifies the good stability of 1 under aerobic conditions.
Importantly, inductively coupled plasma (ICP) analysis performed
on the isolated triazole revealed a negligible contamination by
copper (30 ppm) in agreement with an efficient recovery of the
complex by the solid–liquid separation process. The efficiency and
stability of 1 was further assessed by lowering the catalyst content
(Entries 2–3). At 0.01 mol% loading, the triazole was isolated in
80% yield which represents a turnover number (TN) of 8000.
Using as little as 10 ppm of 1 in neat conditions, the 1,4-
disustituted triazole was still isolated in 54% yield corresponding to
a turnover frequency of 2250 h21 (TN = 54 000 in 24 h). In the
case of the more crowded 1-azido adamantane, a higher catalyst
loading (0.1 mol%) was required to achieve efficient transforma-
tions (Entries 15–17).
In 2004, we reported the preparation and catalytic activity of the
highly crowded [Cu(C186tren)]Br complex 1 in atom transfer
radical polymerization (ATRP) reactions.12,13 The complex 1
proved to be highly reactive in ATRP, whilst an increased
stability towards aerobic conditions was noticed. Whereas most of
the copper(I) catalysts have to be prepared in situ for a given
reaction to avoid decomposition, 1 is conveniently isolated as a
colourless powder by filtration and can be handled in air.
Moreover, 1 exhibits unusual solubility-based thermomorphic
properties in polar solvents such as 1,4-dioxane allowing its
University Bordeaux-1, CNRS-UMR 5255, Institut des Sciences
Mole´culaires, 351 Cours de la libe´ration, 33405 Talence, France.
E-mail: jm.vincent@ism.u-bordeaux1.fr; Fax: +33 (0)5 40 00 61 58;
Tel: +33 (0)5 40 00 89 42
{ Electronic supplementary information (ESI) available: Experimental
data. See DOI: 10.1039/b716306a
This journal is ß The Royal Society of Chemistry 2008
Chem. Commun., 2008, 741–743 | 741

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Table 1 Synthesis of triazoles 4 catalyzed by 1
Entry
R1
R2
Solvent
1 (mol%)
Yielda (%), TNd in parentheses
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
Ph
Ph
Ph
Ph
Ph
SiMe3
t-Bu
Toluene
n-Octane
Neat
0.05
0.01
0.001
0.1
86 (1720)
80 (8000)
54 (54000)
93 (930)
92 (920)
95 (950)
78 (1560)
87 (1740)
65 (1300)
80 (1600)
94 (1880)
78 (1560)
91 (1820)
68 (1360)
62 (620)
Toluene
Toluene
Toluene
n-Octane
n-Octane
Toluene
n-Octane
Toluene
Toluene
Toluene
Toluene
n-Octane
n-Octane
n-Octane
b
—
—
c
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.1
Bn
Bn
CO2Et
n-Bu
10
11
12
13
14
15
16
17
a
m-MeBn
m-MeBn
m-MeBn
m-MeBn
1-Ad
1-Ad
1-Ad
p-MeOC6H4
p-CHOC6H4
CH2OH
CO2Et
Ph
p-CHOC6H4
CO2Et
0.1
0.1
69 (690)
77 (770)
b
c
d
Isolated yields by filtration. Recovered catalyst from entry 4. Recovered catalyst from entry 5. TN = Turnover number.
In 2006, Nolan and coworkers reported examples of 1,3-dipolar
cycloadditions of an internal alkyne (3-hexyne) and benzyl azides
catalyzed by a (NHC)CuBr (NHC = N-heterocyclic carbene)
complex to afford 1,4,5-trisubstituted-1,2,3-triazoles.7a The same
year, Weinreb and Majireck showed that Cp*RuCl(PPh3)2 was a
good catalyst for the [3 + 2] cycloadditions of alkyl azides with
various unsymmetrical internal alkynes.14 Reactions were con-
ducted in refluxing benzene using 10 mol% of the catalyst
affording, depending on the alkynes substituents, the triazoles with
complete regioselectivity. The preliminary result reported in
Scheme 1 reveals the potential of 1 for such transformation.
Indeed, the triazole 7 was isolated in good yield by reacting, in
rather mild conditions, equimolar amount of benzyl azide 5 and
3-hexyne 6 in the presence of 0.5 mol% catalyst. Further studies
will attempt to specifically study the scope of such transformations.
However, it was found that a stoichiometric amount of copper was
needed to achieve high conversions, because the metal remained
trapped in an inactive form inside the dendrimer. Subsequently,
washings with aqueous ammonia were required in the purification
step to remove the copper as [Cu(NH3)6]+ ions. We hypothesized
that the use of 1 in which the copper is caged inside a strongly
coordinating tren ligand could greatly improve the synthesis of
such compounds. As presented in Scheme 2, the dendrimer 9 was
prepared in good yield from the nona-azido precursor 8 using as
low as 0.1 mol% of 1. This corresponds to a 103 times decrease in
copper, with no need for a sacrificial reductant. Moreover the
purification of the dendrimers was achieved by straightforward
solid/liquid phase separation. After the reaction, the rather polar
dendrimer 9 separates from the n-octane solution at low
temperature as a colorless waxy solid sticking the wall of the
flask. By simply removing the liquid phase, 9 was obtained in an
analytically pure form with a copper content of 200 ppm as shown
by ICP analysis.
In conclusion we have shown that
1 is a recyclable,
highly reactive copper(I) catalyst for the Huisgen cycloaddition
of azides with terminal alkynes affording high turnover
numbers under aerobic reaction conditions. The complex 1 also
showed very promising results for the preparation of 1,4,5-
trisubstituted triazoles from internal alkynes. Moreover,
because of its solubility and thermomorphic properties it can
self-separate from the products in an efficient manner.17 In our
previous work on ATRP,12 selective catalyst precipitation
was favoured by running the reactions in a polar solvent,
whilst in this study the use of apolar solvents was preferred to
induce the selective precipitation of the products. We are now
studying the reactivity of 1 in other important Cu(I)-catalyzed
reactions.
Scheme 1 Formation of a trisubstituted triazole catalyzed by 1.
Finally, we also tested 1 as catalyst in the synthesis of a 1,2,3-
triazole-linked dendrimer. The copper(I)-catalyzed ‘‘click’’ reaction
between azides and alkynes has emerged as a powerful synthetic
tool for the preparation and functionalization of dendrimers.15
Recently, Astruc and coworkers successfully exploited such
reaction to prepare the first ‘‘click’’ metallodendrimers bearing
up to 36 internal triazoles and up to 81 ferrocenyl units at the
periphery.16 These dendrimers were used as redox sensors for oxo
anions (H2PO42, ATP22) and transition-metal cations (Pd2+
Cu +/2+) due to coordination to the internal triazoles.
,
The CNRS, the University Bordeaux 1, the Re´gion Aquitaine,
the Institut Universitaire de France are gratefully acknowledged
for their financial support.
For the synthesis of these dendrimers, the ‘‘click’’ reactions
proceeded efficiently using the CuSO4/ascorbate catalytic system.
742 | Chem. Commun., 2008, 741–743
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1 V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
Angew. Chem., Int. Ed., 2002, 41, 2596.
2 C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem., 2002, 67,
3057.
3 (a) R. Huisgen, G. Szeimies and L. Moebius, Chem. Ber., 1967, 100,
2494; (b) R. Huisgen, Pure Appl. Chem., 1989, 61, 613.
4 For a review on the ‘‘click’’ chemistry concept, see: H. C. Kolb,
M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed., 2001,
40, 2004.
5 Reviews on the copper-catalysed triazoles formation: (a) V. D. Bock,
H. Hiemstra and J. H. van Maarseveen, Eur. J. Org. Chem., 2006, 51;
(b) J.-F. Lutz, Angew. Chem., Int. Ed., 2007, 46, 1018.
6 (a) V. O. Rodionov, S. I. Presolski, S. Gardinier, Y.-L. Lim and
M. G. Finn, J. Am. Chem. Soc., 2007, 129, 12696; (b) V. O. Rodionov,
S. I. Presolski, D. Diaz Diaz, V. V. Fokin and M. G. Finn, J. Am.
Chem. Soc., 2007, 129, 12705.
7 (a) S. D´ıez-Gonza´lez, A. Correa, L. Cavallo and S. P. Nolan, Chem.
Eur. J., 2006, 12, 7558; (b) T. R. Chan, R. Hilgraf, K. B. Sharpless and
V. V. Fokin, Org. Lett., 2004, 6, 2853; (c) B. Gerard, J. Ryan,
A. B. Beeler and J. A. Porco, Jr., Tetrahedron, 2006, 62, 6405; (d)
L. Dura´n Pacho´n, J. H. van Maarseveen and G. Rothenberg, Adv.
Synth. Catal., 2005, 347, 811; (e) B. H. Lipshutz and B. R. Taft, Angew.
Chem., Int. Ed., 2006, 45, 8235.
¨
8 (a) C. Girard, E. Onen, M. Aufort, S. Beauvie`re, E. Samson and
J. Herscovici, Org. Lett., 2006, 8, 1689; (b) S. Chassaing, M. Kumarraja,
A. Sani Souna Sido, P. Pale and J. Sommer, Org. Lett., 2007, 9, 883.
9 (a) E. A. Lewis and W. B. Tolman, Chem. Rev., 2004, 104, 1047; (b)
L. M. Mirica, X. Ottenwaelder and T. D. P. Stack, Chem. Rev., 2004,
104, 1013; (c) S. Schindler, Eur. J. Inorg. Chem., 2000, 11, 2311.
10 (a) M. Weitzer, S. Schindler, G. Brehm, S. Schneider, E. Ho¨rmann,
B. Jung, S. Kaderli and A. D. Zuberbu¨hler, Inorg. Chem., 2003, 42,
1800; (b) M. Becker, F. W. Heinemann and S. Schindler, Chem.–Eur. J.,
1999, 5, 3124.
11 (a) M. Schatz, V. Raab, S. P. Foxon, G. Brehm, S. Schneider, M. Reiher,
M. C. Holthausen, J. Sundermeyer and S. Schindler, Angew. Chem., Int.
Ed., 2004, 43, 4360; (b) V. Raab, J. Kipke, O. Burghaus and
J. Sundermeyer, Inorg. Chem., 2001, 40, 6964.
12 G. Barre´, D. Taton, D. Laste´coue`res and J.-M. Vincent, J. Am. Chem.
Soc., 2004, 126, 7764.
13 For a recent review on ‘‘Green’’ ATRP, see: N. V. Tsarevsky and
K. Matyjaszewski, Chem. Rev., 2007, 107, 2270.
14 M. M. Majireck and S. M. Weinreb, J. Org. Chem., 2006, 71,
8680.
15 (a) P. Wu, K. Feldman, A. K. Nugent, C. J. Hawker, A. Scheel, B. Voit,
J. Pyun, J. M. J. Fre´chet, K. B. Sharpless and V. V. Fokin, Angew.
Chem., Int. Ed., 2004, 43, 3928; (b) M. J. Joralemon, R. K. O’Reilly,
J.-B. Matson, A. K. Nugent, C. J. Hawker and K. L. Wooley,
Macromolecules, 2005, 38, 5436; (c) J. W. Lee and B.-K. Kim, Bull.
Korean Chem. Soc., 2005, 26, 658; (d) J. W. Lee, B.-K. Kim, J. H. Kim,
W. S. Shin and S.-H. Jin, J. Org. Chem., 2006, 71, 4988.
16 (a) C. Ornelas, J. Ruiz Aranzaes, E. Cloutet, S. Alves and D. Astruc,
Angew. Chem., Int. Ed., 2006, 45, 1; (b) C. Ornelas, L. Salmon,
J. Ruiz Aranzaes and D. Astruc, Chem.–Eur. J., DOI: 10.1002/
chem.200701410.
17 During the preparation of this manuscript, an example of self-separating
homogeneous copper(I) complexes displaying catalytic activity in ‘‘click’’
triazoles formation and ATRP has been reported: D. E. Bergbreiter,
P. N. Hamilton and N. M. Koshti, J. Am. Chem. Soc., 2007, 129,
10666.
Scheme 2 Formation of a ‘‘click’’ dendrimer catalyzed by 1.
Notes and references
{ General procedure for the 1-catalyzed ‘‘click’’ reactions: In a 2 mL flask
fitted with a stirring bar and a rubber septum, the catalyst 1 (0.01–
0.1 mol%) , the azide (1 mmol) and the alkyne (1 mmol) are stirred in the
desired solvent (1 mL) at 60 uC. After 24 h the flask is placed at 218 uC for
2 h leading to the precipitation of the product which is recovered by
filtration, washed twice and dried under vacuum.
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Chem. Commun., 2008, 741–743 | 743