"Click chemistry" in zeolites: Copper(I) zeolites as new heterogeneous and ligand-free catalysts for the huisgen [3+2] cycloaddition

Article abstract of DOI:10.1002/chem.200800479

For the first time, copper(I)-exchanged zeolites were developed as catalysts in organic synthesis. These solid materials proved to be versatile and efficient heterogeneous, ligand-free catalytic systems for the Huisgen [3+2] cycloaddition. These cheap and

Full text of DOI:10.1002/chem.200800479

FULL PAPER
DOI: 10.1002/chem.200800479
“Click Chemistry” in Zeolites: Copper(I) Zeolites as New Heterogeneous
and Ligand-Free Catalysts for the Huisgen [3+2] Cycloaddition
Stefan Chassaing,[a] Abdelkarim Sani Souna Sido,[a, b] AurØlien Alix,[b]
Mayilvasagam Kumarraja,[a] Patrick Pale,*[b] and Jean Sommer*[a]
Abstract: For the first time, copper(I)-
exchanged zeolites were developed as
catalysts in organic synthesis. These
solid materials proved to be versatile
and efficient heterogeneous, ligand-
free catalytic systems for the Huisgen
[3+2] cycloaddition. These cheap and
easy-to-prepare catalysts exhibited a
wide scope and compatibility with
functional groups. They are very simple
to use, easy to remove (by filtration),
and are recyclable (up to three times
without loss of activity). Investigations
with deuterated alkynes and deuterated
zeolites proved that this CuI-zeolite-
catalyzed “click” reaction exhibited a
mechanism different from that report-
ed for the Meldal–Sharpless version.
Keywords: click chemistry · copper ·
cycloaddition · heterogeneous catal-
ysis · zeolites
Introduction
ed that copper(I) catalysis significantly enhances the cyclo-
addition between alkynes and azides, exclusively affording
1,4-disubstituted 1,2,3-triazoles in very good yields even at
room temperature. Although recent mechanistic aspects
have suggested copper acetylides as key intermediates in
this reaction, the in situ formation of such intermediates is
not unambiguously proven.[6]
With high regioselectivity, 100% atom economy, and con-
venient product isolation, the click version of Huisgen cyclo-
addition has been increasingly used in various applications
ranging from chemical[7] and combinatorial[8] synthesis, bio-
conjugation, and biology[9] to materials science, especially
polymer and dendrimer synthesis.[10] For example, this reac-
tion has been applied to the formation of anti-HIV com-
pounds,[11] selective b3 adrenergic receptor inhibitors,[12] anti-
bacterial compounds,[13] potent antihistaminic compounds,[14]
as well as agrochemicals.[15] 1,2,3-Triazoles themselves have
also found extensive industrial use as corrosion inhibitors,[16]
dyes,[17] and photostabilizers.[18] Furthermore, it is worth
noting that triazoles could become important pharmaco-
phores in future drug discovery because they are stable,
nonharmful, and could mimic peptide bonds from a steric
and electronic point of view, without the same sensitivity to-
wards hydrolytic cleavage.[1b,19]
The “click chemistry” term, first proposed by Sharpless
et al.,[1] has been coined for reactions that: “are modular,
wide in scope, high yielding, create only inoffensive by-prod-
ucts (that can be removed without chromatography), are ste-
reospecific, simple to perform and that require benign or
easily removed solvent.” Not surprisingly, such criteria are
very close to those of green chemistry and, until now, only a
few processes meeting these requirements have been identi-
fied.[1,2] In this context, the copper-catalyzed 1,3-dipolar cy-
cloaddition of alkynes and azides that yields 1,2,3-triazoles
is undoubtedly the premier example of a click reaction.
Originally disclosed by Huisgen, the noncatalyzed cyclo-
addition of alkynes and azides required high temperatures
and usually gave a mixture of regioisomeric triazoles in vari-
able yields.[3] Sharpless[4] and Meldal[5] independently report-
[a] Dr. S. Chassaing, A. Sani Souna Sido, Dr. M. Kumarraja,
Prof. Dr. J. Sommer
Laboratoire de Physicochimie des Hydrocarbures
Institut de Chimie de Strasbourg
4 rue Blaise Pascal, 67000 Strasbourg (France)
E-mail: sommer@chimie.u-strasbg.fr
[b] A. Sani Souna Sido, A. Alix, Prof. Dr. P. Pale
Laboratoire de Synth›se et RØactivitØ Organique
Institut de Chimie de Strasbourg
The copper(I) species required in the catalyzed version of
the Huisgen cycloaddition are either added directly as cupr-
ous salts, usually with stabilizing ligands,[5,20] or more often
generated from copper(II) salts with reducing agents.[4] Met-
allic copper[21] or clusters[22] can also be employed, but al-
though an inexpensive copper source, the corresponding cat-
4 rue Blaise Pascal, 67000 Strasbourg (France)
E-mail: ppale@chimie.u-strasbg.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800479.
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Table 1. CuI-zeolite-catalyzed cycloadditions of benzyl azide 2a with var-
alytic systems present some drawbacks: 1) oxidative agents
are required, 2) reactions are relatively slow, and 3) a signifi-
cant amount of catalyst is necessary. As copper(I) salts are
quite prone to redox processes, nitrogen- or phosphorus-
based ligands must be added to protect and stabilize the
active copper catalyst during the cycloaddition reaction.
Nevertheless, formation of undesired byproducts, primarily
diacetylenes and bistriazoles, was often observed.[4,23]
These problems and the wide applicability of this reaction
led us to explore the possibility of an attractive click-com-
patible heterogeneous version. As click chemistry mediated
by a source of heterogeneous copper(I) is very rare,[21,22,24]
we looked for such catalysts and focused on zeolites in con-
nection with our interest in solid acid-catalyzed chemistry,
as well as in superacid-mediated organic transformations.[25]
In this context, copper(I)-modified zeolites attracted our at-
tention, these solid materials having been recently described
and characterized but surprisingly never used for organic
transformations.[26]
ious alkynes.[a]
Entry Alkyne
1
Product
Yield [%][b,c]
3a 83
1a
1b
1c
1d
2
3
4
3b 76
3c 69
3d 64
3e 85
5
6
7
1e
traces[d]
In continuation of our preliminary results,[27] herein we
report in more detail the scope and limitations of this first
click chemistry in zeolites, as well as some evidence for the
mechanism of this copper(I)-zeolite-catalyzed Huisgen reac-
tion (Scheme 1).
1 f
1g
1h
3 f 89[e]
3g 88
3h 64
8
9
10
11
12
13
1i
1j
1k
1l
3i
3j
83
52[f]
Scheme 1. Copper(I)-zeolite-catalyzed Huisgen reaction.
3k 76[f]
Results and Discussion
Scope and compatibility with functional groups: From a
practical point of view, copper(I)-modified zeolites must
accept a variety of substrates as large as possible, which
have different sizes and carry different functional groups.
Therefore, the scope of the copper(I)-zeolite-catalyzed Huis-
gen reaction was explored with CuI-USY, which proved to
be the best catalyst (see next section and Table 3).
In one series of experiments, terminal alkynes bearing dif-
ferent functional groups 1a–r were submitted to benzyl
azide 2a in the presence of CuI-USY as catalyst (Table 1).
As illustrated by the reaction of 1a and of its substituted an-
alogues 1b–d (Table 1, entries 1–4), aryl substituents allowed
for an efficient cycloaddition, giving the expected adducts
3a–c as single regioisomers in high to excellent yields
(Table 1, entries 1–4). Contrarily to the now “classical” click
reaction,[4,5] electron-donating or -withdrawing groups clear-
ly alter the reactivity of the acetylenic partner. Electron-do-
nating groups decreased yields and the more electron donat-
ing the group, the lower the yield (Table 1, entry 3 vs. 2 vs.
1). The presence of a strong electron-withdrawing group on
the benzene moiety also decreased yields (Table 1, entry 4
vs. 1). These results were reminiscent of the typical delicate
3l
87
14
15
1m
1n
–
–
0[d]
–
–
–
–
0[d]
0[d]
16
17
1o
1p
3m 92
18
19
1q
1r
3n traces[d]
3o traces[d]
20
21
22
1s
1t
1u
–
–
–
–
–
–
–
–
[a] Reagents and reaction conditions: 1 (1.2 equiv), 2a (1.0 equiv), 1m so-
lution concentration, 10 mol% CuI-USY,[31] toluene, 15 h, room tempera-
ture. [b] Yields of isolated pure product. [c] Only the 1,4-adduct was
formed and isolated unless otherwise noted. [d] Mainly recovery of the
starting materials. [e] Reaction performed at 808C. [f] Unidentified by-
products were formed.
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Copper Zeolite Catalysts for the Huisgen Cycloaddition
FULL PAPER
Table 2. CuI-zeolite-catalyzed cycloadditions of phenylacetylene 1a with
balance of frontier orbital controls in the noncatalyzed cy-
cloaddition of azides,[28] but without the associated regiose-
lectivity variations since only 1,4-adducts were produced in
our conditions whatever the alkynes.
various azides.[a]
Alkyl-substituted acetylenes reacted efficiently when the
alkyl chain was linear (Table 1, entry 5), but very slowly at
room temperature when the chain was branched (Table 1,
entry 6). However, at higher temperature, complete conver-
sion was restored and the regioselectivity was still in favor
of the 1,4-adduct, the latter being again the sole product iso-
lated (Table 1, entry 7). Such behavior is not surprising in
zeolites, for which the internal shape dramatically influences
chemical transformations.[29]
Hydroxy-substituted alkynes, such as 1g–i, also gave the
expected adducts 3g–i as single regioisomers in good to high
yields (Table 1, entries 8–10). The conjugated ketone 1j
seemed to decompose under the reaction conditions, even at
room temperature, and byproducts were formed. Even if the
expected triazole could be isolated, the yield of triazole 3j
was therefore lower (Table 1, entry 11). It is worth noting
that terminal ynones are known to be particularly sensitive
compounds.[30] However, the corresponding esters or amides,
1k or 1l, proved fully compatible with the reaction condi-
tions. Although the conjugated amide 1l was converted very
efficiently into the 1,4-disubstituted triazole 3l (Table 1,
entry 13), the ester 1k gave some side products but was still
very effective, giving the triazole 3k in good yield (Table 1,
entry 12).
Entry
1
Azide
Product
Yield [%][b,c]
83
2a
2b
2c
2d
3a
3p
3q
3r
2
3
4
5
91
94
67
76
2e
3s
6
2 f
2g
2h
2i
3t
59
7
3u
3v
3w
3x
61
8
traces[d]
<10[d]
78
9
10
2j
Not surprisingly, free acetylenic acids did not react under
these conditions, even when the acid function was far from
the reactive acetylenic moiety as for 1n (Table 1, entries 14
and 15). The free carboxylic acid function probably interact-
ed with the zeolite framework and the starting materials
were recovered. For similar reasons, free acetylenic amines
did not react (Table 1, entry 16) but protected ones, such as
1p, were easily converted to the expected triazole 3m, again
as a single regioisomer, in excellent yield (Table 1, entry 17).
Acetylenes silylated with either a small or a large group to
scrutinize a possible size discrimination (respectively 1q and
1r) led only to small amounts of the expected triazoles 3n
and 3o (Table 1, entries 18 and 19).
11
2k
3y
63
[a] Reagents and reaction conditions: 1a (1.2 equiv), 2 (1.0 equiv), 1m so-
lution concentration, 10 mol% CuI-USY,[31] toluene, 15 h, room tempera-
ture. [b] Yields of isolated pure product. [c] Only the 1,4-adduct was
formed and isolated unless otherwise noted. [d] Mainly recovery of the
starting materials.
entry 4 vs. 5). Nevertheless, a single regioisomer was still
produced whatever the substitution and yields of isolated
products remained good to excellent (67–94%).
Disubstituted acetylenes, either silylated (1s, 1t) or alky-
lated (1u), did not react under these conditions, the starting
materials being recovered (Table 1, entries 20–22). Note that
only two examples of Cu-catalyzed cycloaddition reactions
of internal alkynes are known so far.[20d,e]
In a second series of experiments, various azides bearing
different groups 2a–k were submitted to phenylacetylene 1a
in the presence of CuI-USY as catalyst (Table 2). Electron-
donating or -withdrawing groups on benzyl azides only
slightly affected the reactivity (Table 2, entries 2–5 vs. 1).
Nevertheless, electron-donating groups slightly favored the
reaction, increasing yields, and it seems that the more elec-
tron donating the group, the higher the yield (Table 2,
entry 3 vs. 2 vs. 1). Electron-withdrawing groups slightly dis-
favored the reaction, lower yields being obtained. Within
these groups, chlorine exhibited the largest effect (Table 2,
In contrast with these results and with those of the first
series (Table 1, entries 2–4 vs. 1), when the phenyl group is
directly linked to the reactive azide, electronic effects are
more pronounced (Table 2, entries 6–8 vs. 1–5) and they sig-
nificantly alter the reactivity. Phenyl azide 2 f or its analogue
with a para-methoxy group 2g gave the expected triazoles
3t and 3u as single regioisomers but with significantly lower
yields than benzyl azide 2a (Table 2, entries 6–7 vs. 1). With
a strong electron-withdrawing group, almost no reaction was
observed and only traces of the expected triazole 3v were
detected (Table 2, entry 8 vs. 6 and 7). In a similar way, tri-
methylsilyl azide 2i yielded only a small amount of the cor-
responding triazole 3w (Table 2, entry 9).
As in the other series (Table 2 versus Table 1), alkyl
azides react very efficiently when they are primary, but
slightly less when they are secondary, both reacting with a
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P. Pale, J. Sommer et al.
very high regioselectivity (Table 2, entries 10 and 11).
Indeed, the single 1,4-adduct 3x was isolated in high yield
from the reaction of 11-azidoundecanol 2j (Table 2,
entry 10), whereas the secondary 2-azidocyclohexanol 2k
only gave the 1,4-disubstituted triazole 3y but in lower yield
(Table 2, entry 11). As before, the bulkiness of the reagents
seemed to affect their reactivity, but not the regioselectivity
of the cycloaddition.
and reused after each run. As shown in Figure 2, the CuI-
USY catalyst could be recycled up to three times without
significant loss of activity (runs 1–3). However, after the
fourth reuse of the catalyst, the catalyst efficiency dramati-
cally decreased (run 5 vs. runs 1–4).
These series of results clearly show that the scope of this
heterogeneous version of the Huisgen “click” reaction is
very broad, the reaction being as compatible with functional
groups as the Meldal–Sharpless version. Moreover, the re-
covery of the products proved to be greatly facilitated, be-
cause filtration and solvent evaporation usually provided
pure 1,4-disubstituted triazoles. The copper(I) zeolite click
reaction is thus often easier and more practical, as well as
more general than the procedures now commonly used for
the Huisgen click reaction.
Figure 2. Recovery studies: cycloaddition of 1a to 2a successively cata-
lyzed by the same recovered CuI-USY.
Catalyst survey: Although protection of copper(I) ions by
zeolite frameworks was already established,[26] we addressed
the question of the stability of such a copper(I) reagent as
catalyst in organic reactions. Keeping the CuI zeolites under
air changed their aspect (color changed from brown to
greenish) but did not alter their reactivity. Indeed, CuI-USY
was still active as catalyst after prolonged air exposure
(Figure 1). It is nevertheless worth noting that in this case,
In parallel, we examined whether leaking of active species
from the zeolite framework is occurring or not. To do so,
CuI-USY was suspended with the reaction solvent (toluene)
and stirred for 2 h, and the resulting suspension was filtered,
which led to a clear and colorless solution. Phenylacetylene
1a and benzyl azide 2a were added. After stirring overnight
at room temperature, the starting materials were the main
compounds identified but the cycloadduct 3a could be de-
tected, although in low amount (ꢀ5%; Figure 3). Control
Figure 1. Influence of the copper(I) zeolite storage on the catalyzed Huis-
gen reaction between 1a and 2a to give 3a.
Figure 3. Leaking studies: comparison of the cycloaddition of 1a to 2a in
the presence of either CuI-USY or a solution resulting from CuI-USY ex-
traction.
undesirable byproducts[32] were detected in small amounts,
slightly lowering yields, contrarily to catalysts not exposed
to air (Figure 1). As a consequence, even if the surface of
the catalyst clearly evolved after prolonged air exposure,
these results clearly showed the effective stabilization of
copper(I) species by the zeolite framework but also suggest-
ed that the reaction is occurring inside the zeolite frame-
work.
Besides ease of handling and purification, another eco-
friendly interesting aspect of heterogeneous catalysts relies
on catalyst recovery and recycling. To look at this aspect, we
performed several times the reaction between 1a and 2a
with the same CuI-USY catalyst, the latter being filtered
experiments revealed that no traces of 3a could be detected
without CuI-USY catalyst or with untreated USY, and thus
it seems that some residual Cu active species are leaking
from the CuI-exchanged USY, catalyzing the cycloaddition
but at a rate by far slower than the CuI-USY-catalyzed reac-
tion (<5 vs. 83% yield after 15 h). The question, under in-
vestigation, is to know whether any leaked CuI species are
coming from the outer surface of the catalyst or from its in-
ternal volume.
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Copper Zeolite Catalysts for the Huisgen Cycloaddition
FULL PAPER
Table 3. Behavior of CuI zeolites in the cycloaddition of 1a to 2a.[a]
Mechanistic investigations: For
a better understanding of this
reaction we embarked on
mechanistic
studies,
and
sought clues on the role of
zeolite structures and on the
mechanism itself.
Entry
Catalyst
Temperature
[8C]
Time
[h]
Yield
[%][b]
Acidic sites
number
Pore diameter
[Š]
Topology type
AHCTREUNG ]
[mmolgÀ1
Zeolites are solid acids
mainly characterized by their
topologies (cage or channel
type), pore size (typically 6 to
8 Š), and acidity (correlated to
the Si/Al ratio).[33] To look for
correlations between structure
and catalytic properties, five
representative zeolites, H-
USY, H-Y, H-MOR, H-ZSM5,
and H-b, were modified by
CuCl treatment according to a
reported solid-state exchange
procedure.[34] Their behavior in
the Huisgen reaction was
screened with the archetypal
cycloaddition of phenylacety-
lene 1a with benzyl azide 2a
(Table 3).
1
2
3
CuI-Y
RT
RT
RT
15
15
15
68
83
69
6.67
4.39
1.48
7.4”7.4
7.4”7.4
6.5”7.0
3.4”3.8
5.1”5.5
5.3”5.6
7.6”6.4
5.5”5.5
7.4”7.4
7.4”7.4
6.5”7.0
3.4”3.8
5.1”5.5
5.3”5.6
7.6”6.4
5.5”5.5
7.4”7.4
cage
cage
channel
CuI-USY
CuI-MOR
4
5
CuI-ZSM5
RT
RT
15
15
63
47
1.04
channel
channel
CuI-b
0.90–1.23
6
7
8
CuI-Y
110
110
110
5
5
5
75
87
79
6.67
4.39
1.48
cage
cage
channel
CuI-USY
CuI-MOR
9
CuI-ZSM5
CuI-b
110
110
RT
5
79
73
1.04
channel
channel
cage
10
11
5
0.90–1.23
6.67
[c]
H-USY
15
–
[a] Reagents and reaction conditions: 1a (1.2 equiv), 2a (1.0 equiv), 1m solution concentration, 10 mol% cata-
lyst,[31] toluene. [b] Yields of isolated pure product 3a after complete conversion unless otherwise stated.
[c] Mainly recovery of the starting materials.
If one considers that copper ions exchanged protons
during CuCl treatment of the zeolite,[34] it was surprising not
to see a clear correlation between the number of active sites
and yields. From 1 to 6 mmolgÀ1, the yields only slightly
varied from 63 to 69% at room temperature and from 73 to
79% at reflux, except for Cu-USY (Table 3, entry 2 vs. 1, 3–
5 and 7 vs. 6, 8–10). At room temperature, the channel-type
zeolites appeared less efficient than the cage-type zeolites
(Table 3, entries 4, 5 vs. 1, 2), the Cu-MOR being neverthe-
less as good as Cu-Y (Table 3, entry 3 vs. 1). As expected,
these differences vanished at reflux, and only Cu-b re-
mained a less effective zeolite whatever the temperature
(Table 3, entries 5 vs. 1–4 and 10 vs. 6–9). Clearly, the modi-
fied USY seemed the best compromise between number of
sites and topology; its efficiency as catalyst was revealed by
a net increase in yields whatever the temperature (Table 3,
entries 2 vs. 1, 3–5 and 7 vs. 6, 9–10). A control experiment
with unmodified USY highlighted the key role of copper
since no transformation occurred under these conditions
(Table 3, entry 11 vs. 2). Therefore, the zeolite framework
alone is not constraining and activating the reagents enough
and no reaction occurred, in contrast to organic encapsulat-
ing systems known to promote the reaction and favor the
1,4-regioisomer in non-copper-catalyzed Huisgen cycloaddi-
tion.[35]
titration to remove adsorbed water and any other molecules
that could have diffused into the zeolite pores.
This H/D titration method proved to be very effective
and allowed us to quantify the number of acidic sites ex-
changed in the copper(I)-modified zeolites. For example,
native USY contained 3.71 mmol of H+ per gram of solid,
but after treatment with CuCl at 3508C, its number of acid
sites decreased to 0.81 mmol of H+ per gram. This result re-
vealed that exchange of H+ by Cu+ indeed took place and
its extent was around 78%.
To get a deeper insight into the mechanism of the present
copper(I)-zeolite-catalyzed reaction, experiments with deu-
terated samples were performed. The mechanism proposed
for the copper(I)-catalyzed Sharpless–Meldal version of the
Huisgen reaction relies on the intermediate formation of
copper acetylides (Scheme 2).[6] Therefore, if such species
Incorporation and stability of copper(I) ions in the zeolite
framework have been established,[26] but we nevertheless
tried to get a better view of the H/Cu exchange process. To
do so, we applied the H/D titration method that we devel-
oped for the determination of acidic sites in zeolites.[31,36]
The catalyst was activated at 3508C under N2 flow prior to
Scheme 2. Proposed mechanism of the copper(I)-catalyzed Sharpless–
Meldal version of the Huisgen reaction.[6]
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P. Pale, J. Sommer et al.
were also formed within zeolites, deuteroalkynes would not
give deuterated triazoles.
these protons could be responsible for the H/D exchange
observed with deuterophenylacetylene.
For this study, the commercially available deuterophenyla-
cetylene 1v was used and submitted to copper(I)-modified
USY. The same experiments were then repeated with a deu-
terated copper(I) zeolite.[37] The results of these experiments
are compiled in Scheme 3.
To check this hypothesis, deuterophenylacetylene 1v was
submitted again to benzyl azide but in the presence of a sto-
ichiometric amount of copper(I) zeolite. In this case, the tri-
azole obtained did not contain deuterium, as expected if H/
D exchange occurred (Scheme 3, [Eq. (2)]).
If the starting zeolite is already deuterated,[37] no H/D ex-
change would be possible and the deuterium label within
the starting material should stay during the reaction if no
other process occurs. As expected, copper(I) zeolite ob-
tained from a deuterated zeolite catalyzed the click reaction
without any loss of deuterium, whatever the amount of cata-
lyst used (Scheme 3, [Eqs. (3) and (4)]). Therefore, this set
of results clearly showed that the mechanism of the zeolite-
catalyzed Huisgen reaction is different from the Meldal–
Sharpless version, and did not involve copper acetylide.
H/D exchanges of terminal alkynes are known to be ac-
celerated in the presence of metal salts, especially with
silver salts. It has been demonstrated that p coordination is
responsible for this effect.[38,39] It is therefore possible that,
within the Cu zeolite framework, formation of a p complex
occurred between the alkyne and copper(I) ions linked to
the zeolite framework (Scheme 4, A). Such coordination
will favor the H/D exchange and thus explains the results
observed (Scheme 3, [Eqs. (1) and (2)]).
Scheme 3. Copper(I)-zeolite-catalyzed cycloadditions with either deuter-
ated alkyne or deuterated zeolite. a) from regular zeolite; b) from deuter-
ated zeolite.
When deuterophenylacetylene 1v was placed in the pres-
ence of benzyl azide in our standard catalytic conditions, the
triazole 3aa was obtained with a yield similar to that ob-
tained with phenylacetylene (see Table 1, entry 1). Interest-
ingly, NMR spectra revealed the presence of vinylic deuteri-
um together with proton, the ratio being in favor of the deu-
terated triazole (60:40; Scheme 3, [Eq. (1)]). The product
was still deuterated after the reaction, and thus the inter-
mediate formation of copper acetylide as suggested in the
“classical” Cu click reaction (Scheme 2)[6] is not the major
pathway in the zeolite version.
Control experiments with deuterated adducts showed that
no exchange occurred in such heterocycles under these con-
ditions (Scheme 3, [Eq. (6)]). However, control experiments
revealed that deuterated phenylacetylene 1v undergoes H/D
exchange (Scheme 3, [Eq. (5)]), probably with residual
acidic protons of the copper(I)-exchanged zeolite. As dem-
onstrated above, the copper(I) zeolite prepared at 3508C
still contains 20% of protons in its active sites. Therefore,
Scheme 4. Proposed mechanism for copper(I)-zeolite-catalyzed cycload-
ditions.
More interestingly, this p coordination helped the under-
standing of what could happen within zeolites. Indeed, fur-
ther coordination of an incoming azide to a copper ion
linked to the zeolite framework could be envisaged. This
would lead to the formation of a new complex where the
triple bond and the azide are coordinated to copper (B in
Scheme 4). This complex could evolve in a process similar
to syn nucleophilic addition to a p complex (for example,
carbocupration). The azide would thus add to the terminal
end of the coordinated alkyne, leading to a metallacycle (C
in Scheme 4). Reductive elimination would then give the tri-
azole adduct, regenerating the copper(I) active species
linked to the zeolite. Note that a similar mechanism has re-
6718
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Copper Zeolite Catalysts for the Huisgen Cycloaddition
FULL PAPER
5.61 ppm (s, 2H); 13C NMR (75 MHz, CDCl3/MeOD 1:1): d=147.9,
146.5, 137.2, 134.9, 129.7, 129.5, 128.7, 126.7, 124.8, 122.5, 54.9 ppm;
HRMS (ESI, positive mode): m/z: calcd for C15H13N4O: 281.1033
[M+H]+; found: 281.1039.
cently been proposed for a Ru-catalyzed version of the click
reaction.[40]
1-Benzyl-4-cyclohexyl-1H-1,2,3-triazole (3 f): By using the general proce-
dure with a reaction temperature of 808C, benzyl azide 2a and 1-ethynyl-
cyclohexane 1 f provided the triazole 3 f as an off-white solid. Yield 89%;
m.p. 1068C; 1H NMR (300 MHz, CDCl3): d=7.39–7.33 (m, 3H), 7.26–
7.23 (m, 2H), 7.14 (s, 1H), 5.48 (s, 2H), 2.78–2.70 (m, 1H), 2.04–2.00 (m,
2H), 1.79–1.68 (m, 4H), 2.04–2.00 (m, 2H), 1.40–1.24 ppm (m, 4H);
13C NMR (75 MHz, CDCl3): d=154.2, 135.0, 129.0, 128.5, 128.0, 119.1,
54.0, 35.3, 33.0, 26.1, 26.0 ppm; HRMS (ESI, positive mode): m/z: calcd
for C15H19N3: 242.1612 [M+H]+; found: 242.1710.
Conclusion
We have shown for the first time that copper(I)-modified
zeolites can be used as catalysts in organic synthesis. With
such catalysts, we have developed a simple and efficient
ligand-free catalytic system for the [3+2] cycloaddition of
terminal alkynes with azides. This heterogeneous method
offers a wide scope, tolerates numerous functional groups,
and provides a very high regioselectivity, with only the 1,4-
disubstituted 1,2,3-triazole regioisomer being formed. More-
over, this heterogeneous copper(I)-modified zeolite catalyst
can be reused three times without loss of activity. Various
investigations suggested a mechanism different from the
click reaction.
4-(1-Benzyl-1H-1,2,3-triazole-4-yl)butan-1-ol (3g): By using the general
procedure, benzyl azide 2a and 5-hexyn-1-ol 1g provided the triazole 3g
as an off-white solid. Yield 88%; m.p. 808C; IR: n˜ =3107, 3056, 4 2931,
2928, 2900, 2861, 1554, 1493, 1453, 1431, 1360, 1332, 1309, 1214 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.33–7.28 (m, 3H), 7.21–7.18 (m, 3H),
5.42 (s, 2H), 3.60 (t, J=6.3 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H), 1.73–1.66
(m, 2H), 1.63–1.51 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=148.4,
134.7, 128.9, 128.4, 127.8, 120.7, 61.8, 53.8, 31.9, 25.4, 25.1 ppm; HRMS
(ESI, positive mode): m/z: calcd for C13H18N3O: 232.1444 [M+H]+;
found: 232.1473.
N-(1-Benzyl-1H-1,2,3-triazole-4-yl)-N-methylbenzylamine
(3m):
By
Experimental Section
using the general procedure, benzyl azide 2a and N-(1-ethynylmethyl)-N-
methylbenzylamine 1p provided the expected triazole 3m as a yellow
solid. Yield 92%; m.p. 528C; IR: n˜ =3038, 3024, 2796, 2758, 1493, 1453,
General: All starting materials were commercial and were used as re-
ceived. The reactions were monitored by thin-layer chromatography car-
ried out on silica plates (silica gel 60 F254, Merck) with UV light and p-
anisaldehyde for visualization. Column chromatography was performed
on silica gel 60 (0.040–0.063 mm, Merck) with mixtures of ethyl acetate
and cyclohexane as eluent. Evaporation of solvents was conducted under
reduced pressure at temperatures less than 308C unless otherwise noted.
Melting points (m.p.) were measured in open capillary tubes and are un-
corrected. IR spectra were recorded with a Perkin–Elmer FTIR 1600
1437, 1418, 1389, 1360, 1329, 1309, 1266, 1220, 1206 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=7.38–7.34 (m, 4H), 7.30–7.24 (m, 7H), 5.52 (s,
2H), 3.69 (s, 2H), 3.52 (s, 2H), 2.21 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=145.9, 138.6, 134.8, 129.1, 129.0, 128.6, 128.2, 128.0, 127.0,
122.3, 61.4, 54.1, 52.1, 42.1 ppm; HRMS (ESI, positive mode): m/z: calcd
for C18H21N4: 293.1761 [M+H]+; found: 293.1738.
11-(4-Phenyl-1H-1,2,3-triazole-1-yl)undecan-1-ol (3x): By using the gen-
eral procedure, 11-azidoundecan-1-ol 2j and phenylacetylene 1a provid-
ed the expected triazole 3x as an off-white solid. Yield 78%; m.p. 1138C;
spectrometer (KBr disk) and values are reported in cmÀ1 1H and
.
13C NMR spectra were recorded on Bruker Avance 300 spectrometer at
300 and 75 MHz, respectively. Chemical shifts d and coupling constants J
are given in ppm and Hz, respectively. Chemical shifts d are reported rel-
ative to residual solvent as an internal standard (chloroform-d1: 7.26 ppm
IR: n˜ =3036, 3009, 2931, 2857, 1719, 1604, 1466, 1433, 1359, 1232 cmÀ1
;
1H NMR (300 MHz, CDCl3/MeOD 1:1): d=8.02 (s, 1H), 7.78–7.75 (m,
2H), 7.44–7.37 (m, 2H), 7.35–7.28 (m, 1H), 4.39 (t, J=7.1 Hz, 2H), 3.52
(t, J=6.8 Hz, 2H), 1.96–1.90 (m, 2H), 1.52–1.45 (m, 2H), 1.40–1.14 ppm
(m, 15H); 13C NMR (75 MHz, CDCl3/MeOD 1:1): d=148.4, 130.9, 129.5,
128.9, 126.3, 121.2, 62.8, 51.2, 33.1, 30.9, 30.3, 30.2, 30.0, 29.6, 29.5, 27.1,
26.4 ppm; HRMS (ESI, positive mode): m/z: calcd for C19H30N3O:
316.2383 [M+H]+; found: 316.2376.
for H and 77.0 ppm for 13C; methanol-d4: 3.31 ppm for H and 49.15 ppm
for 13C). Carbon multiplicities were determined by DEPT135 experi-
ments. Electron impact (EI) and electrospray ionization (ESI) low-/high-
resolution mass spectrometry (HRMS) was carried out at the mass spec-
trometry department of the Service Commun dꢁAnalyses, Institut de
Chimie, Strasbourg.
1
1
2-(4-Phenyl-1H-1,2,3-triazole-1-yl)cyclohexan-1-ol (3y): By using the
general procedure, 2-azidocyclohexan-1-ol 2k and phenylacetylene 1a
provided the triazole 3y as an off-white solid. Yield 63%; m.p. 1778C;
General procedure for the CuI-zeolite-catalyzed [3+2] cycloaddition of
azides and terminal alkynes: Azides 2 (1.3 mmol, 1.0 equiv) and then al-
kynes 1 (1.6 mmol, 1.2 equiv) were added to a suspension of CuI-USY
(50 mg, 0.1 equiv)[31] in toluene (1.5 mL). After stirring for 15 h at room
temperature (unless otherwise stated), the mixture was extracted over-
night with dichloromethane (15 mL). After the catalyst was removed by
filtration, solvent evaporation provided the resulting crude product, usu-
ally at >95% purity as judged by NMR spectroscopy. Column chroma-
tography was performed when necessary.
IR: n˜ =3009, 2946, 2864, 1601, 1484, 1454, 1433, 1353, 1223 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.75 (s, 1H), 7.72–7.68 (m, 2H), 7.40–
7.28 (m, 3H), 4.21–4.03 (m, 2H), 3.55 (d, J=3.7 Hz, 1H), 2.25–2.17 (m,
2H), 2.06–1.88 (m, 4H), 1.53–1.40 ppm (m, 2H); 13C NMR (75 MHz,
CDCl3): d=147.2, 130.5, 128.9, 128.2, 125.7, 119.7, 72.7, 67.2, 33.8, 31.7,
24.9, 24.2 ppm; HRMS (ESI, positive mode): m/z: calcd for
C14H17N3ONa: 266.1264 [M+Na]+; found: 266.1249.
Detailed experimental procedures and NMR spectra of all new com-
pounds and of most of the known compounds are given in the Supporting
Information.
1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (3c): By using the gener-
al procedure, benzyl azide 2a and 1-ethynyl-4-methoxybenzene 1c pro-
vided the triazole 3c as an off-white solid. Yield 69%; m.p. 1458C;
1H NMR (300 MHz, CDCl3): d=7.74–7.70 (m, 2H), 7.57 (s, 1H), 7.41–
7.28 (m, 5H), 6.95–6.90 (m, 2H), 5.55 (s, 2H), 3.82 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=159.6, 148.1, 134.7, 129.1, 128.7, 128.0,
127.0, 123.2, 118.7, 114.2, 55.3, 54.2 ppm; HRMS (ESI, positive mode):
m/z: calcd for C16H15N3O: 266.1248 [M+H]+; found: 266.1234.
Acknowledgements
1-Benzyl-4-(4-nitrophenyl)-1H-1,2,3-triazole (3d): By using the general
procedure, benzyl azide 2a and 1-ethynyl-4-nitrobenzene 1d provided
the triazole 3d as a yellow solid. Yield 64%; m.p. 1688C; IR: n˜ =1601,
A.S.S.S. and M.K. thank the Loker Institute for financial support. The au-
thors gratefully acknowledge financial support from the CNRS and the
French Ministry of Research.
1504, 1456, 1330, 1229, 1107 cmÀ1 1H NMR (300 MHz, CDCl3): d=8.28–
;
8.24 (m, 2H), 7.99–7.95 (m, 2H), 7.80 (s, 1H), 7.43–7.32 (m, 5H),
Chem. Eur. J. 2008, 14, 6713 – 6721
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www.chemeurj.org
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Chem. Eur. J. 2008, 14, 6713 – 6721

Copper Zeolite Catalysts for the Huisgen Cycloaddition
FULL PAPER
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Received: March 14, 2008
Published online: June 23, 2008
Chem. Eur. J. 2008, 14, 6713 – 6721
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6721