Zeo-click synthesis: CuI-zeolite-catalyzed one-pot two-step synthesis of triazoles from halides and related compounds

Article abstract of DOI:10.1016/j.tetlet.2010.05.036

Cu^I-zeolites proved to be an efficient heterogeneous catalyst for the one-pot two-step synthesis of triazoles from halides or tosylates, sodium azide, and alkynes. The step and atom economies of this cascade reaction as well as water used as so

Full text of DOI:10.1016/j.tetlet.2010.05.036

Tetrahedron Letters 51 (2010) 3673–3677
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Zeo-click synthesis: CuI-zeolite-catalyzed one-pot two-step synthesis
of triazoles from halides and related compounds
Valérie Bénéteau a, Andrea Olmos a, Thirupathi Boningari b, Jean Sommer b, Patrick Pale a,
*
a Laboratoire de synthèse et réactivité organiques, associé au CNRS, Institut de Chimie, Université de Strasbourg, 4 rue B. Pascal, 67000 Strasbourg, France
b Laboratoire de Physicochimie des Hydrocarbures, associé au CNRS, Institut de Chimie, Université de Strasbourg, 4 rue B. Pascal, 67000 Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
CuI-zeolites proved to be an efficient heterogeneous catalyst for the one-pot two-step synthesis of tria-
zoles from halides or tosylates, sodium azide, and alkynes. The step and atom economies of this cascade
reaction as well as water used as solvent and catalyst recycling make such synthesis a trully green pro-
cess. With selected substrates, the peculiar roles of CuI-zeolites as catalysts were highlighted.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 14 March 2010
Revised 8 May 2010
Accepted 11 May 2010
Keywords:
Zeolites
Copper
Halides
Catalysis
Water
Triazole
Environmental concern dramatically rose during the last two
decades, leading to the emergence of the concept of ‘Green Chem-
istry’.1 One of the major challenges that chemists are facing today
is the development of new transformations that are not only effi-
cient, selective, and high-yielding but also environmentally benign.
Thus, Green Chemistry aims at the implementation of sustainable
and safe chemical processes, while minimizing wastes production
and energy consumption.
views, this version was still not perfect, being performed in toluene
and with preformed organic azides. We thus tried to combine the
Within this context, we are developing the ‘zeo-click’ synthesis,
that is, organic synthesis based on catalysis with metal-doped zeo-
lites, combining the best of both homogeneous and heterogeneous
catalyses. This new class of heterogeneous catalysts proved easy to
prepare, easy to handle, and recyclable. They can be applied to a
large panel of reaction types for generating various substances
quickly and reliably by regio- and stereoselectively joining small
units together (Scheme 1).2 These useful properties fulfilled most
of the Green Chemistry criteria; they are also close to the chemical
‘philosophy’ introduced by Sharpless in 2001 under the name ‘click
chemistry’.3
The Meldal–Sharpless CuI-catalyzed version4 of the Huisgen
cycloaddition5 between organic azides and terminal alkynes be-
came the archetype of ‘click’-reactions and numerous applications
have since been developed.6 In parallel, we set up an alternative
version using CuI-zeolites as stable and recyclable catalysts
(Scheme 1).2a–c However, from sustainability and safety point of
* Corresponding author. Tel./fax: +33 390 24 15 17.
E-mail address: ppale@chimie.u-strasbg.fr (P. Pale).
Scheme 1. The zeo-click concept and reactions catalyzed by CuI-zeolites.2a–g
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.036

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V. Bénéteau et al. / Tetrahedron Letters 51 (2010) 3673–3677
N
N
R1
R1
R1
R2
R3
Na N3
N
R3
CuI-zeolite
?
CuI-zeolite
R2
N3
R2
X
Scheme 2. CuI-zeolite-catalyzed one-pot reaction of organic halides and related
compounds with sodium azide and alkynes.
organic azide preparation with the cycloaddition in a single zeo-
lite-catalyzed operation run in safer solvents and we reported
herein our results revealing that water was a perfect medium for
such cascade reactions best catalyzed by CuI-USY. A few examples
of such cascade reactions have recently been described,7 including
supported catalyst8 but only two mentioned the use of heteroge-
neous catalyst, that is, copper nanoparticles on carbon or on alu-
mina.9 So far, no example promoted by zeolites has been reported.
Organic azides are usually prepared from the corresponding ha-
lides or related sulfonate species by nucleophilic substitution with
sodium azide. It is worth reminding here that nucleophilic substi-
tution can be accelerated in the presence of various salts, acting as
Lewis acid toward the leaving group.10 CuI-zeolites could therefore
play a dual role, helping at the first nucleophilic substitution step
and catalyzing the second cycloaddition step (Scheme 2).
Figure 1. Recycling of CuI-USY for the reaction between BnBr and phenylacetylene.
for this one-pot two-step transformation, especially at 90 °C (en-
tries 8–10). Interestingly, the observed approximate rates tend to
follow the Grunwald–Winstein relationship12 and related solvent
scales10 defined for SN reaction, suggesting the SN step as the lim-
iting one in this cascade. Furthermore, the higher the ionizing
power of the solvent is,13 the higher is the cascade reaction effi-
cacy, suggesting SN1 type mechanism for the first step.
Benzyl bromide and phenyl acetylene were selected as model
compounds to find the appropriate conditions for the required
CuI-zeolite-catalyzed one-pot synthesis of triazoles from halides.
As CuI-USY often proved to be the best catalyst in other CuI-zeo-
lite-catalyzed reactions,2 we first screened various conditions with
this modified zeolite as the catalyst with an amount of zeolite
doped with copper corresponding to 10 mol % of copper(I) ions11
as in our earlier work (Table 1). For comparison purposes with
our earlier work, we checked the behavior in toluene and in a
few other solvents. As one would expect for SN type reaction, apo-
lar or poorly polar solvents did not allow for any transformation,
whatever the temperature (entries 1–3). More polar solvents
proved more effective (entries 4–10). At room temperature, aceto-
nitrile only gave trace amount of the expected product, while at re-
flux, the conversion remained low (entries 4 and 5). The more polar
DMF gave the cascade product in good yield at room temperature
(entry 6). Under the same conditions, the polar and protic metha-
nol gave better result (entry 7). Water proved to be the best solvent
Under the same conditions, other zeolites were far less effective
as exemplified with CuI-ZSM511 (entry 11) in agreement with our
earlier studies on the ‘click’ step.2a,b These results highlighted the
role played by the zeolite internal structures (channel system for
ZSM5 vs cages for USY) and their Si/Al ratios (15 for ZSM5 vs 3
for USY).
The same reaction with benzyl bromide and phenyl acetylene
was also used for examining the catalyst’s behavior and its role
in each step of the cascade reaction.
Interestingly, the CuI-USY catalyst could be reused four times
without significant yield loss provided the catalyst is reactivated
between each run (Fig. 1).
Due to the aqueous conditions used, leaching of copper(I) spe-
cies could be expected, although the solubility of copper(I) salts
in water is low. This aspect was investigated by premixing CuI-
USY in water at different temperatures and after 20 h, that is, a
time longer than the usual reaction time, and filtration, all reagents
were added to the corresponding solution and their evolution was
monitored. Reaction occurred slowly, revealing that some leaching
was indeed possible especially at 90 °C. However, the oxidation
state of the thus liberated copper species proved important. With
degassed solution and under nitrogen or argon, leaching accounts
for less than 10% of conversion over 20 h depending on the temper-
Table 1
Conditions screening for CuI-zeolite-catalyzed one-pot synthesis of triazoles from
halidesa
N
NaN3
N
N
Ph
Ph
Ph
Br
CuI-zeolite
Ph
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Cu-USY
Cu-USY
Cu-USY
Cu-USY
Cu-USY
Cu-USY
Cu-USY
Cu-USY
Cu-USY
Cu-USY
Cu-ZSM5
Tol
Tol-THF
THF
MeCN
MeCN
DMF
MeOH
H2O
20–110
20–70
20–70
20
80
20
20
20
50
90
15
15
15
15
15
15
15
15
15
15
20
0c
0c
Scheme 3. CuI-USY role in nucleophilic substitution with sodium azide.
0c
Traces
22c
71
R1
80
50d
60d
98
R2
R2
OH
N3
H2O
H2O
H2O
R1
H2O
10
11
R3
23d
N
N
90
R1
Na N3
CuI-zeolite
R1
R2
R2
X
N
a
R
The reaction was conducted under anoxic conditions.
Isolated yields of pure product after complete conversion unless otherwise
3
b
CuI-zeolite
stated.
c
Scheme 4. CuI-zeolite role in the one-pot cascade reaction between sodium azide,
alkyne and halide.
The starting materials were recovered.
d
Mixture of benzyl derivatives was also recovered.

V. Bénéteau et al. / Tetrahedron Letters 51 (2010) 3673–3677
3675
Table 2
One-pot CuI-zeolite-catalyzed synthesis of triazoles from halides and related compoundsa
Entry
Halide
BnCl
Alkyne
Triazole
Yieldb
1
2
0
Ph
N
N
62c
N
Ph
Bn
Bn
3
BnBr
90
Ph
Ph
N
N
N
Ph
4
5
28
BnOTs
N
N
58c
N
Ph
Bn
6
7
BnOTf
BnBr
Ph
—
0d
98
pCF3Ph
N
N
N
pCF3Ph
pCH3Ph
nHex
Bn
Bn
8
BnBr
89
pCH3Ph
nHex
N
N
N
9
BnBr
BnBr
75
72
N
N
N
Bn
OH
N
N
10
N
Bn
OH
11
12
BnBr
58
73
N
N
HO
Ph
HO
Cl
N
Bn
Cl
N
Br
N
N
N
Cl
Br
Cl
Ph
13
88
Ph
N
N
N
N
N
Br
90:10
77:33
Ph
Ph
14
15
0
Ph
Ph
N
N
57e
EtBr
N
Ph
Et
16
17
0
N
N
64e
PrI
N
Ph
Pr
N
18
19
61
80
Ph
N
MeOOC
Br
N
N
MeOOC
O
Ph
O
Ph
Ph
N
Br
N
Ph
Ph
Ph
20
21
62
N
N
87c
N
Br
Ph
22
0
Ph
—
Br
a
b
c
The reaction was conducted under anoxic conditions (see the general procedure below).
Yields of isolated pure products.
Performed in a 1:1 mixture of water and ethanol.
Decomposition was observed.
d
e
Performed in a 1:1 mixture of water and dioxane.

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V. Bénéteau et al. / Tetrahedron Letters 51 (2010) 3673–3677
ature, while in the presence of air, this increased to 20%. Not so sur-
prisingly, leaching is thus more or less important according to the
solubility of copper ions in water.
giving higher yield of triazoles (entries 14–17). Solubility prob-
lems again required the addition of a co-solvent in these cases.
However,
a-bromo keto derivatives such as methyl 2-bromoace-
Knowing the CuI-zeolite-catalyzed cycloaddition step,2a–c we
investigated in more detail the first substitution step, that seemed
to be the limiting step as shown above. This was performed by
comparing the reaction of sodium azide and benzyl bromide alone
in the presence or not of CuI-USY. Unexpectedly, the solvolysis
product, that is, benzyl alcohol, was the major product isolated un-
der both conditions (Scheme 3). This reaction was almost quantita-
tive without catalyst, while some by-products could be detected in
the presence of CuI-zeolite, among which was the expected benzyl
azide, accounting for around 5–10% of the whole mixture.
These interesting results suggested that in the presence of CuI-
zeolite, the azide and the bromide are forced to react together,
probably through confinement into zeolite cages, while without
zeolite, the major but less reactive nucleophile present, that is,
water, led to the product. It is worth noting that the amount of
benzyl azide observed in these experiments corresponded to the
zeolite copper(I) loading (10%), suggesting a stoichiometric nucle-
ophilic substitution promoted by copper(I) under these conditions,
as for Ag-assisted nucleophilic substitutions.14 These results also
revealed that equilibrium or competitive reactions occurred and
are shifted if alkyne is also present in the mixture, suggesting a
more SN1 than any other type mechanism (Scheme 4).
tate or bromo-acetophenone proved readily reactive in pure
water and gave the corresponding triazoles in good to high
yields (entries 18 and 19).
Secondary bromides reacted better than their primary counter-
parts. In pure water, the triazole derived from 2-bromobutane was
produced in good yield, and in high yield when a co-solvent was
added (entries 20 and 21 vs 14 and 15). The better results achieved
with secondary bromides compared to those from similar primary
ones supported again SN1 rather than SN2 or any other substitution
mechanism for the first step of this cascade reaction.
Unfortunately, tert-butyl bromide led to mixtures of products,
while adamantyl bromide remained untouched (entry 22). For
the former, decomposition and/or elimination seemed to be the
major processes whatever the conditions. For the latter, the rigid
and bridgehead structure of adamantyl bromide prevents substitu-
tion through SN2 mechanism and barely limits SN1 reaction. At
least, the absence of product and solvolysis product ruled out
any other substitution mechanism under the present conditions.
In conclusion, we have developed a CuI-zeolite-catalyzed one-
pot synthesis of triazoles from halides or tosylates, sodium azide,
and alkynes. The step and atom economy of this cascade reaction
as well as the green solvent used make such one-pot two-step syn-
thesis a truly green process. The results obtained suggest for the
first step a SN1 mechanism in which the CuI-doped zeolite plays
several roles, first as the Lewis acid, second as the solid solvent,
probably stabilizing cation intermediates, and third as the entropic
driver through confinement effect.16
With these results in hands, we then looked at the scope of this
CuI-zeolite-catalyzed one-pot synthesis of triazoles from halides
and related compounds (Table 2).
We first screened different electrophiles, classically used in
nucleophilic substitutions for comparison with bromides. Benzyl
chloride was not reactive in water whatever the temperature (en-
try 1). However, despite a lower polarity and ionizing power of the
solvent,12,13 the cascade reaction occurred in rather good yield if
ethanol was added as the co-solvent, although less efficiently than
starting from benzyl bromide (entry 2 vs 3). Solubility problem
was thus clearly responsible for the lack of reactivity. Benzyl tosyl-
ate also proved to be not so reactive in pure water but more reac-
tive than benzyl chloride since the expected triazole was isolated
although in low yield (entry 4 vs 1). In water–ethanol mixture, a
similar yield was now achieved (entry 5 vs 2). In contrast to ha-
lides, no solvolysis product could be detected under these reac-
tions. The corresponding triflate was too sensitive for practical
use (entry 6).
General procedure: To a suspension of CuI-USY (20 mg/mmol) in
degassed water (2 mL/mmol) under argon were successively added
sodium azide (1.1 equiv), the halide or tosylate (1 equiv), and the
alkyne (1 equiv). The mixture was then heated to 90 °C overnight
(15 h). When no alkyne could be detected, the mixture was al-
lowed to cool and then filtered over NylonÒ membrane (0.2
lm).
The solid was rinsed with water and ethyl acetate. The aqueous
phase was then extracted with ethyl acetate. The organic layer
was then dried and the solvent evaporated. The resulting crude
mixture was then purified by chromatography.
Acknowledgments
Being the best starting material, benzyl bromide was used to
screen various alkynes. The triazoles corresponding to the ex-
pected cascade reaction were usually obtained in good to excellent
yields (entries 7–11). The results were consistent with those ob-
served in the zeo-click reaction from preformed azides.2a–c
More functionalized benzyl bromides could also be efficiently
engaged in this cascade reaction. For example, o,o0-dichlorobenzyl
bromide gave the corresponding triazole in high yield, despite the
hindrance brought by the two large ortho substituents (entry 12).
Allylic bromide reacted as well as its benzyl counterpart. Inter-
A.O. thanks the CNRS for a post-doctoral fellowship. V.B. also
thanks the CNRS for a ‘delegation’ fellowship. T.B. thanks Dr. M.
B. Reddy and the Franco-Indian exchange program for a fellowship.
The authors thank the CNRS, the French Ministry of Research and
the Loker Institute for founding.
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-product (entry 13). This classical product spread10 suggested
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a
c
a
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was more or less effective depending on the substitution at
the halogenated carbon. Primary halides reacted as expected,
the iodide being more reactive than the corresponding bromide,

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