A highly active and magnetically recoverable tris(triazolyl)-CuI catalyst for alkyne-azide cycloaddition reactions

Article abstract of DOI:10.1002/chem.201304536

Nanoparticle-supported tris(triazolyl)-CuBr, with a diameter of approximately 25 nm measured by TEM spectroscopy, has been easily prepared, and its catalytic activity was evaluated in the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. In in

Full text of DOI:10.1002/chem.201304536

DOI: 10.1002/chem.201304536
Full Paper
&
Click chemistry
A Highly Active and Magnetically Recoverable Tris(triazolyl)–CuI
Catalyst for Alkyne–Azide Cycloaddition Reactions
Dong Wang,[a] Laetitia Etienne,[b] Marꢀa Echeverria,[c] Sergio Moya,[c] and Didier Astruc*[a]
Abstract: Nanoparticle-supported tris(triazolyl)–CuBr, with
a diameter of approximately 25 nm measured by TEM spec-
troscopy, has been easily prepared, and its catalytic activity
was evaluated in the copper-catalyzed azide–alkyne cycload-
dition (CuAAC) reaction. In initial experiments, 0.5 mol%
loading successfully promoted the CuAAC reaction between
benzyl azide and phenylacetylene, in water at room temper-
ature (258C). During this process, the iron oxide nanoparti-
cle-supported tris(triazolyl)–CuBr displayed good monodis-
persity, excellent recoverability, and outstanding reusability.
Indeed, it was simply collected and separated from the reac-
tion medium by using an external magnet, then used for an-
other five catalytic cycles without significant loss of catalytic
activity. Inductively coupled plasma (ICP) analysis for the first
cycle revealed that the amount of copper leached from the
catalyst into the reaction medium is negligible (1.5 ppm).
The substrate scope has been examined, and it was found
that the procedure can be successfully extended to various
organic azides and alkynes and can also be applied to the
one-pot synthesis of triazoles, through a cascade reaction in-
volving benzyl bromides, alkynes, and sodium azide. In addi-
tion, the catalyst was shown to be an efficient CuAAC cata-
lyst for the synthesis of allyl- and TEG-ended (TEG=triethy-
lene glycol) 27-branch dendrimers.
Introduction
restricts the application of such systems in electronics and bio-
medicine. To overcome this drawback, a wide range of strat-
egies have been investigated. Chromatographic purification of
the crude product, washing the crude product with ethylene-
diaminetetraacetic acid (EDTA) or ammonia, and performing
CuAAC reactions under continuous flow conditions (quadra-
pureTM, thiourea resin, or activated charcoal as the metal scav-
enger) are all acceptable methods, but they are scavenger-,
energy-, and time-consuming procedures. The development of
an astute copper-free click strategy has been proposed, but
this strategy has only been used for the CuAAC reactions of cy-
clooctyne reagents.[9] The heterogenization of click-chemistry
catalysts appears to be a logical solution; the use of heteroge-
neous catalysts could results in easy removal, recovery, and re-
usability of the copper catalyst; thereby, minimizing copper
contamination of the reaction products. Until now, several sup-
ports have been employed for immobilization of copper spe-
cies, such as polymers,[10] zeolites,[11] activated carbon,[12] alumi-
na,[11a,13] resin,[14] carbon nanotubes,[15] and silica.[16]
The copper-catalyzed 1,3-dipolar cycloaddition reaction be-
tween alkynes and azides (CuAAC), yielding 1,4-disubstituted
1,2,3-triazoles,[1] is undoubtedly the most representative exam-
ple of a “click” reaction[2] to date. The CuAAC reaction demon-
strates excellent atom economy, exclusive regioselectivity,
a high tolerance to a range of functional groups, and the use
of mild reaction conditions. In addition, 1,2,3-triazoles possess
many interesting properties, such as antibacterial,[3] antialler-
gic,[4] anti-HIV,[5] and antineoplastic[6] activity. 1,2,3-triazoles also
have the potential for coordinating to metal centers, which
can be useful for sensing and in further catalytic reactions.[7]
Therefore, the CuAAC reaction has been extensively applied in
organic synthesis, biology, and materials science[8] since its dis-
covery by the groups of Sharpless[1a] and Meldal[1b] in 2002.
However, the majority of reported CuAAC systems, in partic-
ular the systems that use homogeneous catalysts, have been
susceptible to contamination by the cytotoxic CuI ion, which
In a related context, functionalized magnetic nanoparticles
have emerged as viable alternatives.[17] Magnetic nanosized
catalysts can easily be separated from reaction mixtures by
using an external magnet. They display better stability and re-
usability, more efficient catalytic activity, lower preparation
costs, and lower toxicities in comparison with other materials
that are used as supported heterogeneous catalysts. These
properties are due to their insoluble, paramagnetic, and nano-
sized nature.[18] In addition, the size, shape, morphology, and
dispersity of magnetic nanosized catalysts are controllable.
Therefore it is possible to design different magnetic nanocata-
lysts for specific catalytic applications.[19]
[a] Dr. D. Wang, Prof. Dr. D. Astruc
ISM, Universitꢀ Bordeaux
351 Cours de la Libꢀration, 33405 Talence Cedex (France)
E-mail: d.astruc@ism.u-bordeaux1.fr
[b] L. Etienne
ICMCB, UPR CNRS No. 9048
87 Avenue, Pey-berland, 33608 Pessac Cedex (France)
[c] M. Echeverria, Prof. S. Moya
CIC biomaGUNE, Unidad Biosuperficies
Paseo Miramꢁn 182, Edif. “C”, 20009 Donostia-San Sebastiꢂn (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304536.
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Among the various copper sources for CuAAC reactions, in-
cluding CuII salt/reductant mixtures, CuI salts, copper nanopar-
ticles, CuI complexes, and Cu0/oxidant mixtures, CuI complexes
represent the most efficient copper source in terms of product
yield and catalyst turn-over numbers (TONs). The use of CuI–
and the reusability of the catalyst, for CuAAC reactions, have
been investigated.
ligand complexes was shown to both accelerate the catalytic Results and Discussion
process, in comparison with the ligand-free CuI species, and
Synthesis of magnetic iron oxide nanoparticle-supported
stabilize CuI intermediates. Moreover, it is relatively straightfor-
ward to graft CuI complexes onto a support in hybrid material
assemblies. Indeed, nitrogen-based ligands and N-heterocyclic
carbenes (1a–e, Figure 1) were found to be excellent ligands
tris(triazolyl)–CuI complexes
The primary step for the synthesis of the iron oxide nanoparti-
cle-supported tris(triazolyl)–CuI complexes was the synthesis of
tris(1-benzyl-1H-1,2,3-triazol-4-yl)methanol, 1e (Scheme 1). The
CuAAC reactions were conducted, in the presence of copper
sulfate and sodium ascorbate (a catalytic system developed by
Sharpless et al.),[1a] between three equivalents of benzyl azide
and a tris(alkynyl)carbinol intermediate. This intermediate was
readily prepared by the addition of trimethylsilylacetylide to
ethyl chloroformate, followed by removal of the trimethylsilyl
(TMS) groups. The 3-chloropropyltriethoxysilane-functionalized
magnetic nanoparticles, 2, were obtained through immobiliza-
tion of 3-chloropropyltriethoxysilane on the surface of robust
[23]
SiO2/g-Fe2O3 by means of heterogenization with the SiꢀOH
binding sites of SiO2/g-Fe2O3 in toluene heated at reflux. Mag-
netic nanoparticle-supported tris(1-benzyl-1H-1,2,3-triazol-4-yl)-
methanol, 3, was prepared by alkylation of 2 with 1e.[14b] The
loading of 3 was calculated by determination of the nitrogen
content (C, H, N elemental analysis), the result indicated that
the content was approximately 0.068 mmolgꢀ1. Finally, com-
plexation of 3 with CuCl or CuBr (1.1 equivalents) resulted in
the assembly of magnetic nanoparticle-supported tris(triazol-
yl)–CuCl, 4a, or tris(triazolyl)–CuBr, 4b, respectively. Transmis-
sion electron microscopy (TEM) images showed that the diam-
eter of 4b was approximately 25 nm (Figure 2a).
Figure 1. A selection of ligands currently used in CuAAC reactions.
Cy=cyclohexyl; Mes=mesityl; Pr=n-propyl; Ad=adamantyl.
for CuAAC reactions.[20] Fokin et al. designed polytriazoles 1d
that showed outstanding activity for click reactions with vari-
ous substrates.[21a,b] Subsequently, Pericꢂs et al. prepared tris(1-
benzyl-1H-1,2,3-triazol-4-yl)methanol ligand, 1e, and CuCl-1e,
which efficiently catalyzed CuAAC reactions in water, or under
neat conditions, in a short reac-
tion time with a low catalyst
loading. In addition, the hydroxyl
group of 1e proved to be a very
promising anchoring point for
immobilization, allowing the
assembly of heterogeneous
CuAAC catalysts.[21c] Our group
synthesized CuI complexes with
(hexabenzyl)tren 1b, and den-
dritic analogues with 18- or 54-
branch termini that are powerful
catalysts for click reactions. The
catalytically active metalloden-
drimers provided a rare positive
dendritic effect that was also
mechanistically very useful.[22]
Herein, we present the synthesis
of a magnetic CuI-1e complex,
in which 1e was not only used
as the chelating framework for
the CuI salt, but also as a linker
to SiO2-coated g-Fe2O3 nanopar-
ticles. Both the catalytic activity Scheme 1. Synthesis of CuX-1e/SiO2/g-Fe2O3 (4). Bn=benzyl.
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Investigation of the reusability of 4b in the CuAAC reaction
between benzyl azide and phenylacetylene
The reusability of the highly active magnetic nanoparticle-sup-
ported CuI complex, 4b, was tested by using the model reac-
tion between benzyl azide and phenylacetylene, with
0.5 mol% [Cu] in water at room temperature, under a nitrogen
atmosphere. Catalyst 4b showed excellent magnetic properties
and monodispersity. After completion of the first reaction, the
catalyst was collected by using an external magnet, successive-
ly washed with CH2Cl2 and methanol, and dried under vacuum
for 2 h. A new reaction was then performed with fresh reac-
tants under the same conditions. The results are summarized
in Table 2; 4b could be reused six times without significant
Figure 2. a) TEM image of CuBr-1e/SiO2/g-Fe2O3 (4b) before the CuAAC reac-
tions; b) TEM image of 4b after eight reaction cycles. Scale bars=200 nm.
Optimization of the conditions for alkyne–azide
cycloadditions catalyzed by 4
The catalytic applications of magnetically recyclable catalyst 4
in the cycloaddition reaction between benzyl azide and phe-
nylacetylene, yielding the corresponding 1,4-disubstituted
1,2,3-triazoles, was investigated under various conditions
(Table 1). In these preliminary experiments, CuAAC reactions
Table 2. Reusability test for catalyst 4b in the cycloaddition reaction be-
tween phenylacetylene and benzyl azides.[a]
Run
Yield [%][b]
Yield [%][c]
1
2
3
4
5
6
7
8
97
95
94
92
92
92
84
67[d]
96
93
72
39
–
–
–
–
Table 1. Screening of solvents and catalysts for CuAAC.[a]
[a] The reaction was carried out with phenylacetylene (1 mmol) and
benzyl azide (1.05 mmol) in the presence of 4b (74 mg, 0.005 mmol
copper), at room temperature in water for 20 h. [b] Isolated yields after
column chromatography. The reaction was carried out in nitrogen-
purged H2O (for 10 min) under a nitrogen atmosphere. [c] Isolated yields
after column chromatography. The reaction was carried out in air. [d] The
reaction time was 45 h.
Entry Cat. ([mol%]) Solvent Ratio ([mL]:[mL]) Time [h] Yield [%][b]
1
2
3
4
5
6
7
8
4a (0.17)
4a (0.2)
4a (0.5)
4a (1)
4a (1)
4a (1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
EtOH/H2O (1:1)
H2O (1)
4
24
68
24
24
24
12
20
28
61
98
91
90
90
89
97
4b (0.5)
4b (0.5)
H2O (1)
H2O (1)
loss of its catalytic activity, a decrease in the yield of the reac-
tion only being observed after six cycles. The TEM image re-
vealed that the morphology and size of 4b changed over
time, and a particle aggregation problem emerged after eight
reaction cycles (Figure 2b). In addition, the leaching of copper
species from the initial catalyst into the reaction media, a key
issue for evaluating heterogeneous catalysts for CuAAC reac-
tions, was investigated. After the first cycle, inductively cou-
pled plasma (ICP) analysis revealed that 0.04% of copper spe-
cies was released from the initial catalyst into the reaction
media, and the amount of residual copper species in the crude
reaction product was approximately 1.5 ppm, compared with
5–15 ppm for other catalysts in the literature.[7,8] Thus, copper
species leaching into the crude product was not completely
eliminated, but appeared to be negligible.[17c] As anticipated,
the tris(triazolyl) fragment proved to be a stable chelating
framework for the adsorption of the CuI salt, and a good linker
for the SiO2-coated g-Fe2O3 nanoparticles through straightfor-
ward CꢀO bond formation. Magnetic catalyst 4b also per-
formed well in the presence of air, but became deactivated
after the second run, probably caused by aerobic oxidation of
the CuI species into a CuII species.
[a] The reaction was carried out with phenylacetylene (1 mmol) and
benzyl azide (1.05 mmol) in the presence catalysts 4a or 4b, in the stated
solvent at room temperature, under a nitrogen atmosphere. [b] Isolated
yields after column chromatography.
were conducted in a mixture of MeOH and H2O (1:1), with vari-
ous loadings of 4a, under a nitrogen atmosphere at room tem-
perature. Increasing yields of 1,2,3-triazoles were obtained with
increasing catalyst loading, in the range 0.17–1.0 mol%. The re-
actions proceeded in excellent yields (91%) in the presence of
1 mol% 4a (entry 4), and replacing the mixed solvent MeOH/
H2O by H2O alone or by EtOH/H2O did not affect the catalytic
efficiency. Catalyst 4b was then evaluated in CuAAC reactions
and demonstrated superior catalytic activity compared with
that of 4a (0.5 mol% 4b provided 1,2,3-triazoles with 97%
yield, in water, within 20 h at room temperature) Considering
our goal of an economic and environmentally friendly reaction,
these aqueous conditions are clearly favorable. Moreover, the
excellent catalytic performances of 4a and 4b benefited from
the good monodispersity of the SiO2-coated iron oxide nano-
particles in water.
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We then questioned whether CuBr did not coordinate with
the tris(triazolyl) ligand to form a copper complex, but was
simply caged in the iron oxide nanoparticles. In order to
answer this point, a control experiment was performed by
mixing SiO2-coated g-Fe2O3, without the tris(triazolyl) ligand,
with CuBr (three equivalents according to the amount of CuBr
used in synthesis of 4b).[14b] The obtained mixture was used
for promoting the cycloaddition reaction of benzyl azide with
phenylacetylene. To achieve a clear comparison, the amount of
the mixture corresponded to the weight of 4b at the same
scale. The results showed that a 54% yield was obtained in the
first run, and only 18% in the second run. Therefore, it is rea-
sonable to infer that the iron oxide supported tris(triazolyl)–
CuBr complex is the actual catalytic species.
and the corresponding 1,2,3-triazoles, 5e and 5 f, were ob-
tained in 86 and 92% yields, respectively. The somewhat lower
yield of the former reaction is probably attributable to the rela-
tively bulky structure. Aliphatic alkynes containing linear chains
were also suitable substrates, producing 1,4-disubstituted
1,2,3-triazoles 5g and 5h in excellent yields (99 and 93%, re-
spectively). It was found that longer-chain aliphatic terminal al-
kynes resulted in the lowest yields. The products 5i and 5j
were separated with high conversions when aliphatic terminal
alkynes with hydroxyl groups were employed in CuAAC reac-
tion. This procedure has been successfully extended to include
ferrocenylacetylene as a substrate, the yield of the obtained
product, 5k, being 96%. The reusability of 4b was also verified
with all substrates, as shown in Figure 3.
The substrate scope of organic azides was then further in-
vestigated (Figure 4). The results indicated that benzyl, alkyl,
and aryl azides could be successfully employed to assemble
1,2,3-triazoles through the CuAAC reaction with phenylacety-
lene. The yields decreased steadily upon increasing the alkyl-
chain length of the organic azides (6a–6c). When phenyl azide
was used, 4b smoothly promoted the formation of 1,2,3-tria-
zole 6d with a 92% yield. However, organic azides with elec-
tron-donating (CH3) or electron-withdrawing (I) substituents re-
sulted in lower yields. For each substrate, 4b was recovered
Investigation of the substrate scope for CuAAC reactions
catalyzed by 4b
Encouraged by the efficiency of the reaction protocol de-
scribed above, the scope of the reaction was examined with
magnetic catalyst 4b (0.5 mol% [Cu]), in water under a nitro-
gen atmosphere, at room temperature. Firstly, various terminal
alkynes were investigated in reactions with benzyl azide. For
each substrate, the reusability of 4b was examined for the first
three runs. As shown in Figure 3, on carrying out the CuAAC
reaction between benzyl azide and phenylacetylene on
a 0.25 mmol scale, the desired 1,4-disubstituted 1,2,3-triazole,
5a, was produced in 96% yield with 100% selectivity (the se-
1
lectivity was determined by using H NMR spectroscopy), and
a slight decrease in the yield was observed from runs one to
three (down to 92%). Electron-donating (CH3O, NH2) and elec-
tron-withdrawing (CHO) groups on the alkynes were tolerated,
and no direct correlation could be drawn between the elec-
tronic nature of the terminal alkynes and the outcome of the
reaction. Heteroatom-containing alkynes, 2-ethynylpyridine
and 3-ethynylpyridine, were suitable cycloaddition partners,
Figure 4. Substrate scope of organic azides in the presence of catalyst 4b.
The bar graph shows the yield of isolated products. 6a: R2 =C6H13 (yield of
the first three runs: 95, 92, and 90%); 6b: R2 =C8H17 (91, 88, and 88%); 6c:
R2 =C18H37 (82, 74, and 74%); 6d: R2 =C6H5 (92, 92, and 88%); 6e: R2 =4-
CH3OC6H4 (83, 81, and 80%); 6 f: R2 =4-IC6H4 (81, 77, and 72%).
and reused three times with good catalytic activity.
Cascade-reaction strategies display significant advantages
over classical stepwise methods and have frequently been
used as a powerful method in organic synthesis. Cascade reac-
tions offer rapid and convergent construction of molecules
from commercially available starting materials, without the iso-
lation and purification of any intermediates, resulting in saving
time, cost, and energy. In this context, taking into account the
interest in avoiding storage and manipulation of organic
azides, which can be hazardous, a three-component one-pot
process was investigated by testing an azido reaction/1,3-dipo-
lar cycloaddition of alkynes, sodium azide, and benzyl bro-
mides (Figure 5). This process performed smoothly with
Figure 3. Substrate scope of terminal alkynes in the presence of catalyst 4b.
The bar graph shows the yield of isolated products. 5a: R1 =C6H5 (yield of
the first three runs: 96, 95, and 92%); 5b: R1 =4-CHOC6H4 (96, 95, and
90%); 5c: R1 =4-CH3OC6H4 (94, 94, and 88%); 5d: R1 =4-NH2C6H4 (92, 90,
and 85%); 5e: R1 =pyridine-2-yl (86, 84, and 80%); 5 f: R1 =pyridine-3-yl (92,
91, and 91%); 5g: R1 =C4H9 (99, 94, and 94%); 5h: R1 =C5H11 (93, 87, and
86%); 5i: R1 =HOC(CH3)2 (89, 84, and 84%); 5j: R1 =HOC(C6H5)2 (93, 91, and
87%); 5k: R1 =ferrocenyl (96, 87, and 85%).
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Conclusion
The syntheses of iron oxide nanoparticle-supported tris(triazol-
yl)–CuI complexes, 4, has been shown to be straightforward
and convenient. The CuBr version of the magnetic nanoparticle
catalyst, 4b, showed, with low loading (0.5 mol%), good cata-
lytic activity, recoverability, and reusability in CuAAC reactions.
The catalyst was easily separated from the reaction medium by
using an external magnet and showed good catalytic activity
for six cycles. The amount of leaching copper species from the
initial catalyst into the reaction media, determined by induc-
tively coupled plasma (ICP) analysis, is negligible. This system
has a broad substrate scope, and 25 1,4-disubstituted 1,2,3-tri-
azoles were synthesized in good to excellent yields, including
27-allyl and 27-TEG dendrimers. For each small molecular sub-
strate, 4b was reused three times with either the same catalyt-
ic efficiency or only a slight decrease in yield. The outstanding
performance of 4b benefited from the excellent inherent prop-
erties of iron oxide nanoparticles and the powerful chelating
nature of the tris(triazolyl) ligand with CuI centers. The above-
mentioned results show that the reported procedure is easy-
to-operate, economical, and environmentally friendly, as well
as being in accordance with the principles of click chemistry
and green chemistry. Magnetic catalyst 4b could potentially
be applied to CuAAC reactions for the synthesis of macromole-
cules, biomolecules, and nanoparticles.
Figure 5. One-pot azide formation and subsequent CuAAC reaction mediat-
ed by 4b. 7a: R3 =4-Br (yield of the first three runs: 88, 84, and 84%); 7b:
R3 =3-I (87, 86, and 83%); 7c: R3 =4-CN (72, 60, and 56%); 7d: R3 =4-NO2
(90, 87, and 87%); 7e: R3 =3-CH3 (98, 96, and 90%); 7 f: R3 =1-CH2-4-C6H5-
1H-[1,2,3]triazole (83, 82, and 72%).
0.5 mol% 4b, without other additives, in water for 24 h at
room temperature. Both electron-donating (3-CH3) and elec-
tron-withdrawing (4-Br, 3-I, and 4-NO2) substituents on benzyl-
bromide showed good reactivity with sodium azide and phe-
nylacetylene, producing the corresponding 1,2,3-triazoles in ex-
cellent yields. When 4-cyano benzylbromide was involved in
the reaction, a lower yield (72%) was obtained, attributable to
the coordination behavior of 4-cyano benzylbromide with the
active copper center, resulting in deactivation of the catalyst.
The double-azido CuAAC reaction of 1,2-dibromomethyl-ben-
zene proceeded well in the presence of 1 mol% 4b, yielding
product 7 f, which contains two triazole fragments, in 83%
yield, and only a trace amount of the single triazole product.
The reusability of 4b was also investigated in the cascade-reac-
tion strategy. Thus, it was shown that 4b could be recovered
and reused three times with only a slight decrease in the yield
of the reaction. We also attempted the same tandem reactions,
but with a linear-chain alkyl bromide (1-bromooctane), sodium
azide, and phenylacetylene. Unfortunately, only a trace of de-
sired product was obtained, probably because of the poor re-
activity of 1-bromooctane with sodium azide in water at room
temperature. Also, no triazole was produced when an aryl bro-
mide (phenyl bromide) was employed, owing to the inability
of phenyl bromide to undergo SN2 reactions.
Experimental Section
General
All reactions were performed under nitrogen by using standard
Schlenk techniques, unless otherwise noted. DMF was freshly dis-
tilled from calcium hydroxide, 1,4-dioxane was dried over Na foil,
and distilled from sodium benzophenone under nitrogen immedi-
ately prior to use. CuBr was purified by stirring in glacial acetic
acid overnight, followed by filtration, washing with ethanol and
then drying under vacuum; it was stored under nitrogen and in
the dark. All commercially available reagents were used as re-
ceived, unless indicated otherwise. Flash column chromatography
was performed using silica gel (300–400 mesh). 1H NMR spectra
were recorded by using a 300 MHz spectrometer, and 13C NMR
spectra were recorded at 75 MHz by using a 300 MHz spectrome-
ter. Elemental analyses were performed by the Center of Microanal-
yses of the CNRS at Lyon Villeurbanne, France. The infrared spectra
were recorded on an ATI Mattson Genesis series FTIR spectropho-
tometer. The inductively coupled plasma optical emission spectros-
copy (ICP-OES) analyses were carried out using a Varian ICP-OES
720ES apparatus. Room temperature throughout the paper is 23–
258C.
Encouraged by the efficiency of the reaction protocol de-
scribed above, 4b was probed as a CuAAC catalyst for the syn-
thesis of 27-branch dendrimers by 1!3 connectivity between
dendritic nona-azide polymer 8 and two propargylated phenol
dendrons (9a and 9b). In a previous report,[8e,24] it was indicat-
ed that these reactions reached completion only in the pres-
ence of a quantitative amount of the catalyst developed by
Sharpless et al. We found that 8 mol% of 4b per branch suc-
cessfully catalyzed the quantitative synthesis of 27-allyl and 27-
TEG dendrimers (10a and 10b, respectively) over 26 h or two
days, respectively (Scheme 2). Moreover, after the first cycle of
the synthesis of 10a, 4b was recharged and completed anoth-
er synthesis of 10a, within approximately three days, under
ambient conditions.
Synthesis of tris(triazolyl)methanol (1e)[21c]
A solution of trimethylsilylacetylene (2.3 mL, 16.6 mmol) in anhy-
drous THF (20 mL) was cooled to ꢀ788C. Then, 2.5m nBuLi in
hexane (6.1 mL, 15.2 mmol) was added dropwise, and the solution
was stirred for 4 h. Ethyl chloroformate (442 mL, 4.61 mmol) was
added, and the reaction was stirred overnight while warming to
ꢀ308C. The reaction was quenched with saturated NH4Cl solution,
diluted with water, and extracted with Et2O (3ꢃ30 mL). The com-
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Scheme 2. Synthesis of dendrimers 10a and 10b through CuAAC reactions catalyzed by 4b.
bined organic phase was dried over Na2SO4, and the solvent was
removed under reduced pressure. The crude product was further
purified by silica-gel chromatography (petroleum ether/ethyl ace-
tate as eluent) to yield tris(trimethylsilylethynyl)methanol in 67%
tion of benzyl azide (1.25 g, 9.40 mmol) in methanol (10 mL).
CuSO4 5H2O (38.9 mg, 0.156 mmol) and sodium ascorbate (93.0 mg,
.
0.468 mmol) were added, and the mixture was stirred for 14 h at
room temperature. The solvent was removed under reduced pres-
sure. The residue was dissolved in dichloromethane (50 mL) and
washed with saturated Na2CO3 solution (5ꢃ30 mL). The organic
phase was dried over Na2SO4 and the solvent removed under re-
duced pressure. Purification was performed by flash column chro-
matography, with petroleum ether/ethyl acetate as eluent, and
1
yield (1.0 g). H NMR (300 MHz, CDCl3): d=2.82 (s, 1H), 0.18 ppm (s,
27H).[21c] In a round-bottomed flask, the obtained tris(trimethylsily-
lethynyl)methanol in methanol (10 mL) was stirred in the presence
of K2CO3 (4.20 g, 37.5 mmol) at room temperature overnight. The
solution was filtered to remove excess K2CO3 and added to a solu-
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1
product 1e was obtained in 37% yield (0.58 g). H NMR (300 MHz,
ganic phase was dried over Na2SO4 and filtered, the filtrate was re-
moved under reduced pressure in order to obtain the crude prod-
uct, which was further purified by silica-gel chromatography (pe-
troleum ether/ethyl acetate as eluent) to yield the corresponding
1,4-disubstituted 1,2,3-triazole. The recovered catalyst was then
used for the next reaction cycle.
CDCl3): d=7.64 (s, 3H), 7.24–7.38 (m, 15H), 5.47 (s, 6H), 5.04 ppm
(s, 1H).[21c]
Synthesis of iron oxide nanoparticle-supported
tris(triazolyl)methanol ligand (3)[14b]
A solution of 1e (252 mg, 0.5 mmol) in DMF (2 mL) was added
dropwise into a suspension of NaH (15 mg) in anhydrous DMF Acknowledgement
(2 mL) at 08C. After stirring for 45 min at room temperature, the
suspension became a clear solution and was cooled to 08C and
Helpful discussions with Dr. J. Ruiz and financial support from
the added through a syringe to a sonicated DMF solution of 2
(400 mg). The reaction mixture was allowed to warm to room tem-
perature, and dried at 808C for 96 h. After this time the reaction
mixture was cooled down to room temperature, and the magnetic
solid was separated by using an external magnet and then succes-
sively washed with DMF (20 mL), THF (20 mL), MeOH (20 mL), and
Et2O (20 mL). The resulting magnetic nanoparticles were dried in
a vacuum at 458C overnight. The amount of tris(triazolyl) ligand in
the functionalized magnetic nanoparticles, 3, was 0.068 mmmol
the China Scholarship Council (CSC) of the People’s Republic of
China (Ph. D. grant to D.W.), the Universitꢄ de Bordeaux, and
the Centre National de la Recherche Scientifique (CNRS) are
gratefully acknowledged.
Keywords: click chemistry
· copper · green chemistry ·
magnetic nanoparticles
g
ꢀ1, which was calculated from the results of elemental nitrogen
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Received: November 19, 2013
Published online on && &&, 0000
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FULL PAPER
&
Click chemistry
D. Wang, L. Etienne, M. Echeverria,
S. Moya, D. Astruc*
&& – &&
A Highly Active and Magnetically
Recoverable Tris(triazolyl)–CuI Catalyst
for Alkyne–Azide Cycloaddition
Reactions
Magnets make it easy: Magnetically re-
coverable tris(triazolyl)–CuI catalysts
have been synthesized for the prepara-
tion of 1,2,3-triazoles (see figure). These
catalysts display high activity, easy re-
coverability, and efficient reusability. Re-
actions are performed under aqueous
reaction conditions and a broad sub-
strate scope is demonstrated. These cat-
alysts can also be applied to a one-pot
synthesis of triazoles by means of a cas-
cade reaction.
Chem. Eur. J. 2014, 20, 1 – 9
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9
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ