Sol-gel entrapped Cu in a silica matrix: An efficient heterogeneous nanocatalyst for Huisgen and Ullmann intramolecular coupling reactions

Article abstract of DOI:10.1016/j.apcata.2015.05.025

A recyclable catalytic system has been developed that comprises an inorganic polymer matrix consisting of non-functionalized silica, which encapsulates copper by direct interaction with the matrix. Cu is fixed to a silica support of nanometric dimensions by physical entrapment within a silica sol-gel matrix. Samples with different Cu loadings were studied in order to maximize and optimize the amount of entrapped Cu within the silica matrix. This entrapment limits the diffusion of the metal to the solution, thus ensuring negligible contamination of the product by the metal while simultaneously providing a stabilizing environment. This robust and versatile heterogeneous catalyst was evaluated in Huisgen and Ullmann intramolecular coupling reactions.

Full text of DOI:10.1016/j.apcata.2015.05.025

Applied Catalysis A: General 502 (2015) 86–95
Contents lists available at ScienceDirect
Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
Sol–gel entrapped Cu in a silica matrix: An efficient heterogeneous
nanocatalyst for Huisgen and Ullmann intramolecular coupling
reactions
a
a,c
a
c
a
Paula Diz , Paula Pernas , Abdelaziz El Maatougui , Carmen R. Tubio , Jhonny Azuaje ,
a,b
c
c,∗
a,b,∗∗
Eddy Sotelo , Francisco Guitián , Alvaro Gil , Alberto Coelho
Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
Department of Organic Chemistry, Faculty of Pharmacy, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Institute of Ceramics, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A recyclable catalytic system has been developed that comprises an inorganic polymer matrix consisting
of non-functionalized silica, which encapsulates copper by direct interaction with the matrix. Cu is fixed
to a silica support of nanometric dimensions by physical entrapment within a silica sol–gel matrix. Sam-
ples with different Cu loadings were studied in order to maximize and optimize the amount of entrapped
Cu within the silica matrix. This entrapment limits the diffusion of the metal to the solution, thus ensur-
ing negligible contamination of the product by the metal while simultaneously providing a stabilizing
environment. This robust and versatile heterogeneous catalyst was evaluated in Huisgen and Ullmann
intramolecular coupling reactions.
Received 27 March 2015
Received in revised form 18 May 2015
Accepted 23 May 2015
Available online 29 May 2015
Keywords:
Sol–gel
Heterogeneous catalysis
CuAAC
©
2015 Elsevier B.V. All rights reserved.
Ullmann
1
. Introduction
catalysts in many fundamental reactions (e.g., coupling reactions,
oxidations and hydrogenations). However, the application of this
approach in areas such as pharmaceutical and agrochemical indus-
tries remains limited due to the difficulties in meeting the strict
controls established by the regulatory agencies in relation to the
amounts of metals in medicines and pesticides (generally low ppb
range) [2]. In addition to the aspects described above, there are
other factors such as intrinsic reactivity and instability of the cat-
alytic species that impose particular experimental conditions (e.g.,
Metal-catalyzed reactions occupy a prominent place among the
synthetic methods of Organic Chemistry. These transformations
allow efficient access to wide range of complex structures using
mild and environmentally friendly experimental conditions. Much
of the progress made in this area has followed the development
of the homogeneous or heterogeneous catalysts that are available
today. Both catalytic systems have characteristic advantages and
disadvantages. In homogeneous catalysis, the catalyst is soluble in
the reaction medium and this usually results in a more efficient
catalytic process and a high selectivity. However, this approach
does suffer from the problems of separation of the catalyst from the
reaction mixture and recycling. As a result, heterogeneous cataly-
sis is preferred for industrial-scale processes [1], mainly due to the
ability to recover and reuse the catalyst and the avoidance of con-
tamination of the final products by toxic transition metals used as
+
Cu ), thus limiting the extensive application of these systems.
One of the most successful strategies in this area involves the
heterogenization of the catalytic species by immobilization into
organic [3–6] (e.g., polystyrene or dendrimers) or inorganic [7,8]
(e.g., silica, zeolites or Al O ) polymeric materials. In particular,
2
3
catalysis with metal-doped silicates is an emerging technology that
is of increasing interest for the scientific community [9–11]. The
structural features of silica make it an excellent support for cat-
alytic applications, particularly when compared to conventional
supports (e.g., organic-based polymers). Although they have been
extensively employed, organic matrices have intrinsic limitations
as catalyst supports. For example, their functionality can be highly
dependent on the solvent (swelling) and this can seriously affect
reaction rates. Moreover, these supports can only host a relatively
low catalyst loading and the weak ligation of metallic species
could allow some leaching of the catalytic species, particularly
∗
∗
Corresponding author.
Corresponding author at: Center for Research in Biological Chemistry and Molec-
∗
ular Materials (CIQUS), University of Santiago de Compostela, 15782 Santiago de
Compostela, Spain.
E-mail addresses: alvaro.gil@usc.es (A. Gil), albertojose.coelho@usc.es
(
A. Coelho).
http://dx.doi.org/10.1016/j.apcata.2015.05.025
926-860X/© 2015 Elsevier B.V. All rights reserved.
0

P. Diz et al. / Applied Catalysis A: General 502 (2015) 86–95
87
when highly coordinating solvents and elevated temperatures are
employed. Silica supports work under a wide range of experimen-
tal conditions – in both organic and aqueous solvent systems –
and they are easy to handle, do not suffer from static issues and
are readily amenable to automation. In addition, silica is mechani-
cally stable, works in any format, is easily scaled and requires little
washing because it does not swell in any solvent. The entrapment
of catalytic species within sol–gel silica matrixes not only permits
facile recycling of the catalyst, but also provides a stabilizing envi-
ronment that increases the catalytic activity. At the same time, this
entrapment protects the catalyst from redox changes and incom-
patible chemicals, thus allowing multistep one-pot reactions to be
carried out with entrapped catalysts in the presence of entrapped
catalyst poisons [12,13]. Some recent examples with PdCl (PPh )
and Pd(PPh3)4 have highlighted the potential of this field [14,15].
The abundance and increasing applications of copper-catalyzed
reactions demand novel active and recyclable immobilized cop-
per(I) catalysts. Two good examples of reactions in which copper(I)
plays a central role are the well-established Huisgen Copper
Alkyne-Azide Cycloaddition (CuAAC) [16–21] and the Ullmann
reaction [22]. A current trend in these transformations is the het-
erogenization of the catalyst [23–34]. While current methodologies
represent major progress in this field, challenges associated with
the synthesis, reactivity and leaching profiles of these catalytic sys-
tems remain partially unsolved. In particular, the long and tedious
synthetic procedures generally employed for the heterogeniza-
tion of copper preclude the widespread use of these conventional
heterogeneous catalytic systems. However, interesting approaches
have been performed in the preparation of new nanostructured
copper-based systems [35–42]. Despite the extraordinary simplic-
ity offered by the sol–gel method for the effective trapping of
metallic species in silica [43], only three studies concerning the syn-
Na SO . Solvents were dried and purified by standard methods.
2 4
All reactions were monitored by TLC with 2.5 mm Merck silica
gel GF 254 strips and the purified compounds showed a single
spot. Detection of compounds were performed by UV light and/or
iodine vapour. The synthesis, isolation and purification of CuAAC
compounds were accomplished using the equipment for paral-
lel synthesis. A PLS (6 × 4) Organic Synthesizer was used for the
synthesis of compounds. Ullmann reactions were performed in an
Anton Paar Microwave (Monowave 300) synthesizer. Isolation of
precipitated/triturated products was performed in a 12-channel
vacuum manifold from Aldrich. Chromatographic purification was
carried out by preparative TLC. The synthesized compounds were
characterized by spectroscopic and analytical data. The NMR spec-
1
13
tra were recorded on Bruker AM300 MHz ( H) and 75 MHz ( C) and
XM500 spectrometers. Chemical shifts are given as ı values against
tetramethylsilane as internal standard and J values are given in Hz.
2
3 2
1
13
Proton and carbon nuclear magnetic resonance spectra ( H,
C
NMR) were recorded in CDCl . Melting points were determined on
3
a Gallenkamp melting point apparatus and are uncorrected. EPR
experiments were performed on a Bruker EMX spectrometer. Mass
spectra were obtained on a Varian MAT-711 instrument. High-
resolution mass spectra (HR-MS) were obtained on an Autospec
Micromass spectrometer. Inductively coupled plasma mass spec-
troscopic (ICP-MS) analysis of compounds 3a, 3b and 8d was
performed on a Varian 820-MS spectrometer (after microwave-
assisted digestion of the samples). The morphology of the SiO –Cu
2
catalyst was observed by Scanning Electron Microscopy (SEM, JEOL
6400) and by Transmission Electron Microscopy (TEM, JEOL JEM-
1011). The surface of the SEM sample was coated with gold (∼200 A˚
thickness) prior to imaging in order to minimize charging. Energy
Dispersive Spectrometry (EDS) elemental analysis of the catalyst
was carried out on an Oxford INCA instrument attached to a scan-
ning electron microscope in the scanning range 0–10 keV.
thesis and study of SiO –Cu materials have been reported [44–46].
2
While these references provided a proof of concept, several facets
of these catalytic materials remain unexplored. In particular, the
optimization of the synthesis (copper loading levels), the exhaus-
tive study of the leaching of the metal from the polymeric matrix
and the extension of this approach to other transformations must
be addressed. In the context of a programme aimed at the devel-
opment of novel polymer-supported catalytic systems [47–50], we
report here the synthesis, characterization and study of the catalytic
activity of a novel catalytic system consisting of copper species
entrapped within the inner pores of a non-functionalized silica
matrix. The presence of copper in the silica matrix leads to a cat-
alyst with high microporosity [43,51]. Additionally, the inorganic
matrix provides chemical, thermal and mechanical stability, which
gives rise to a highly robust encapsulated nanocatalyst that displays
the benefits of both homogeneous and heterogeneous catalysts.
Furthermore, the material exhibits excellent catalytic activity and
selectivity in different reactions and solvents, produces negligi-
ble leaching of the catalytic species to the reaction media and can
be easily recovered and recycled. For these reasons, this catalyst
exemplifies the concept of semi-heterogeneous catalyst [52].
2.2. Synthesis of SiO –Cu catalyst
2
The SiO –Cu catalyst described here was obtained in a one-
2
pot procedure using a modified sol–gel process by the addition of
copper iodide during a hydrolysis/condensation reaction of a non-
functionalized tetra-silicon alkylalkoxide. This procedure led to
metal immobilization within the silica matrix, with the metal phys-
ically entrapped as the polymeric system grew. The catalyst was
prepared by a modified Stöber method [53] as follows: a mixture of
NH OH (7.47 mL), H O (1.59 mL) and absolute ethanol (87.11 mL)
4
2
was stirred at room temperature in a 500 mL conical flask. TEOS
(3.83 mL) was added dropwise to the above solution. 5 min after
the addition of TEOS the mixture turned white and the required
amount of CuI was slowly added to the solution. SiO –Cu catalysts
2
with different Cu contents were prepared in order to optimize the
loading of Cu in the silica matrix. Different amounts (0.02, 0.05, 0.10,
0.20, 0.30, 0.40, 0.50, and 0.80 g) of CuI were added to the hydroly-
sis/condensation reaction of the SiO . The mixture was stirred for
2
1
2 h at room temperature and was then centrifuged at 3000 rpm
for 15 min and washed by repeated redispersion three times in
pure ethanol and three times in deionized water. The precipitate
was dried at 45 C overnight. The final sample was a fine blue pow-
2
. Experimental
◦
2.1. General remarks
der. Bare SiO2 particles were synthesized by the same procedure
as used for SiO –Cu but without the addition of CuI. The catalyst
2
Commercially available reagents and starting materials were
purchased and used from containers without further purification.
Tetraethyl orthosilicate (TEOS, 99.0%) was purchased from Fluka.
was subjected to a final treatment. The catalyst (1 g, blue powder)
was suspended in a solution of sodium ascorbate (40 mL, 0.5 M) in
water and stirred for 24 h. The colour of the catalyst changed from
light blue to green and finally evolved into a greyish colour (see
Fig. 4). The material was filtered off, washed with Milli-Q water
and diethyl ether, dried in an oven and stored under vacuum prior
Absolute ethanol (reagent grade) and ammonia (25.0% NH OH solu-
4
tion in water) were purchased from Merck. Water was purified
in a Milli-Q filtration unit from Millipore Co. and had a resisti-
vity of 18.2 Mꢀ cm. Organic extracts were dried with anhydrous
to use in the reactions. All compounds were characterized by 1
H

8
8
P. Diz et al. / Applied Catalysis A: General 502 (2015) 86–95
NMR and 13C NMR spectroscopy and by HRMS. The spectroscopic
data are provided in the supporting information.
2.7. Hot filtration test for Ullmann intramolecular coupling
reaction
Twin experiments (A and B) with 5-fluoro-bromophenol
2.3. General procedure for the CuAAC reaction employing
(5b) (0.6 mmol), 2-chloro-N-(4-ethoxyphenyl) acetamide (6b)
SiO –Cu in DMF or t-BuOH/H O, using organic azides and alkynes
(0.5 mmol), potassium carbonate (1 mmol) and the SiO –Cu (33 mg,
2
2
2
(
Method A)
10 mol% Cu) catalyst in DMF (5 mL) were carried out for 20 min
at 100 C under MW heating. After this time, both transforma-
◦
To an equimolar mixture (1 mmol) of acetylenic derivative and
the corresponding organic azide in dimethylformamide (5 mL) [or
a mixture of t-BuOH/H O (3:1)] was added diethylisopropylamine
tions had reached approximately 50% conversion (TLC control:
AcOEt/Hexane, 1:2). In one of the experiments (A), the solids
2
(SiO –Cu catalyst and potassium carbonate) were removed by hot
2
(
3 mmol) and SiO –Cu (32 mg, 0.05 mmol Cu). The reaction mixture
filtration using a preheated hot syringe and the filtrate was trans-
ferred to another Kimble vial and 1 mmol of potassium carbonate
was added. Heating was continued in both reactions for 1 hour
and the reactions were assessed by TLC (AcOEt/Hexane, 1:2). Reac-
tion A gave only the intermediate compound 7d (70% yield, and
2
was stirred at room temperature for 3–5 h and filtered. The filtrate
was evaporated to dryness and the corresponding 1,4-substituted
1
,2,3-triazole was purified by chromatographic methods.
only traces of compound 8d). Experiment B (containing SiO –Cu
catalyst) gave 8d in 83% yield.
2
2.4. General procedure for CuAAC (3 component version) reaction
employing SiO –Cu in t-BuOH/H O (Method B)
An inductively coupled plasma-mass spectrometry (ICP-MS)
study of the obtained filtrates showed that the copper loss
from the catalyst was negligible. ICP-MS analysis for filtrates of
compound 3a: 0.2003 ± 0.0231 ppb. 3b: 0.1009 ± 0.0200 ppb. 8d:
0.1007 ± 0.01110 ppb.
2
2
SiO –Cu (32 mg, 0.05 mmol Cu) was added to an equimolar mix-
2
ture (1 mmol) of the acetylene derivative and the corresponding
alkyl halide, sodium azide and diethylisopropylamine (3 mmol) in a
3
:1 mixture of t-BuOH/H O (6 mL). The reaction mixture was stirred
2
at room temperature for 3–6 h. The catalytic system was removed
by filtration and the product was extracted with diethyl ether and
dried under reduced pressure. The solution was filtered and the fil-
trate was evaporated to dryness. The corresponding 1,4-substituted
3. Results and discussion
3.1. Design, synthesis and characterization of the SiO –Cu
2
1
,2,3-triazole product was then purified.
catalyst
We initially focussed on the synthesis of the catalytic system
by entrapment of copper species within the silica matrix through
the sol–gel method. Physical entrapment, in addition to providing a
stabilizing environment for copper species, is expected to limit the
diffusion of such species to the solution, thus avoiding contamina-
tion of products with traces of metal. With the aim of developing
catalysts that would be applicable to a wide range of synthetic
transformations, different copper sources (e.g., CuCl, CuI, CuNO2
2
.5. General procedure for the synthesis of
2
H-1,4-benzoxazin-3-(4H)-ones
A 5 mL process vial was charged with 2-bromophenol (5a)
(
0.6 mmol), 2-chloroamide 6a (0.5 mmol), SiO –Cu (33 mg, 10 mol%
2
Cu), Cs CO (1.0 mmol) and DMF (5 mL). The vessel was sealed
under N and exposed to microwave heating for 60–90 min at
1
2
3
2
◦
00 C. The reaction tube was cooled to room temperature and
or CuSO ) were initially evaluated by considering parameters such
4
ethyl acetate (20 mL) was added. The resulting suspension was fil-
tered. The filtrate was concentrated and the residue was purified by
column chromatography on silica gel (Hex/EtOAc = 4:1–2:1, v/v) to
give the desired product 8a. The identity and purity of the products
was confirmed by H and C NMR spectroscopic analysis and by
HRMS.
as catalytic performance, oxidation state, solubility and price. Two
sources (CuI and CuSO ) were selected for preliminary exploration
4
by a slight modification of Stöber’s method [53]. It was gratify-
ing to find that, irrespective of the copper source, the modified
sol–gel procedure (see experimental part) afforded the targeted
catalytic systems as pale blue particles. The process is straight-
forward, experimentally simple, and delivered nanoparticles with
yields greater than 80%. Modification of the reaction conditions
allowed modulation of both the concentration of copper species
1
13
2.6. Hot filtration test for CuAAC
(
0.45–12.83%) and the dimensions (90–150 nm) of the particles.
In two Kimble vials, twin CuAAC experiments (A and B) using
It should be highlighted that the catalytic system described here
did not contain functionalized spacers, since the copper species are
attached to the solid support by physical entrapment between the
polymer chains, which are synthesized during the hydrolytic poly-
merization that produces the material. As the evaluated copper
sources (CuI and CuSO ) provided particles with similar physical
appearance and copper loading, we subsequently focussed on the
study of catalytic systems obtained with CuI.
benzyl azide (1 mmol) and phenylacetylene (1 mmol) in DMF (5 mL)
were performed in the presence of the SiO –Cu catalyst (32 mg,
2
0
.05 mmol Cu). Once the transformations had reached 50% com-
pletion (TLC control: AcOEt/Hexane 1:3), the catalyst was removed
from one of the reactions (experiment A) by hot filtration of the
solids through a preheated syringe and the solids were then washed
with hot solvent (5 mL). The clear solution containing the filtrate
and the washings was allowed to react further in the absence
of solids in another Kimble vial. Both reactions (experiments A
and B) were stirred for 8 h and the same work up described
4
The morphologies of bare SiO2 and the resulting SiO –Cu
2
catalyst were analyzed by SEM and TEM. The micrographs of bare
SiO2 and the SiO –Cu catalyst are displayed in Fig. 1a–d. Bare SiO2
particles (Fig. 1a) are monodisperse non-aggregated spheres with a
2
above was applied to the other reaction containing SiO –Cu cat-
2
alyst (experiment B). The filtrates were evaporated to dryness and
the corresponding 1,4-substituted 1,2,3-triazole then purified. The
yields of the Huisgen products 3a in the two reactions – with and
without solid catalyst – were compared (experiment A = 52% yield;
experiment B = 90% yield).
mean diameter of 250 nm, whereas the SiO –Cu catalyst (Fig. 1b–d)
shows how the addition of CuI to the hydrolysis/condensation
reaction of SiO2 changed the morphology and size of the SiO2
2
particles. These images reveal that the SiO –Cu is composed of a
2
dense agglomerate of polydisperse nanoparticles with an average

P. Diz et al. / Applied Catalysis A: General 502 (2015) 86–95
89
Fig. 1. SEM micrographs of (a) bare SiO2, (b) SiO2–Cu catalyst (9.4 wt.% Cu) and TEM micrographs (c, d) of SiO2–Cu catalyst (9.4 wt.% Cu).
diameter of less than 100 nm. Details of the coalesced particles are
shown in Fig. 1c and d.
the catalytic performance of the system. Additionally, such porosity
facilitates the movement of reactants through the polymeric matrix
to the immobilized catalyst and also the return of the product(s) to
the solution once the reaction has taken place.
As previously documented, the presence of the Cu species during
the gelation process favours microporosity, thus increasing the spe-
cific area of the silica matrix [43,51]. As can be seen in the images,
large pores are observed between the masses. These macropores
also facilitate the diffusion of the reactants through the catalyst.
The EDS results (Fig. 2) unequivocally confirm the encapsulation
of the Cu within the hybrid catalyst and elements other than Cu,
Si and O were not detected in the samples. The porous nature of
the polymeric structure provides a large surface area on which the
metal compounds can be trapped, thereby increasing the distribu-
tion of the catalyst within the nanoparticle matrix and enhancing
In order to determine the efficiency of the copper entrapment
during the synthesis of the catalysts, a preliminary study was car-
ried out with variable quantities of CuI (0.02, 0.05, 0.10, 0.20, 0.30,
0.40, 0.50 and 0.80 g). In all syntheses the other reactants and
solvent quantities were kept constant. The quantitative determi-
nation of the fraction of entrapped Cu in the inorganic matrix was
measured by ICP. In agreement with previous EDS determinations
(Fig. 2), the ICP studies confirmed the presence of Cu in the cata-
lysts. Quantitative analysis confirmed that catalytic systems were
obtained with variable loadings (0.05–9.4 wt.%) of the encapsulated
metal. The results were compared graphically with the theoretical
weight fraction assuming that 100% of the added Cu was entrapped
(Fig. 3). It can be seen from Fig. 3 that for levels of less than 9.4 wt.%
of entrapped Cu, the weight fraction of entrapped Cu is practically
identical to the calculated value. This indicates that all of the CuI
added was trapped in these cases. Above 9.4 wt.% of entrapped Cu,
the fraction between free Cu and trapped Cu increases to the same
extent as the increase in the added CuI. Therefore, the optimal
amount of added CuI for the synthesis conditions described was
0
.4 g, which corresponds to 9.4 wt.% of entrapped Cu.
The catalytic systems obtained in this work had a characteris-
tic pale blue colour regardless of the copper source employed in
the synthesis, and this physical appearance suggests the promi-
nence of Cu(II) species. Samples of both materials were analyzed by
EPR. These studies unequivocally confirmed the presence of cupric
species within these materials, thus indicating that CuI is oxidized
during the sol–gel procedure. The pale blue appearance of the cat-
alyst and the characteristic intense EPR signal for paramagnetic
Fig. 2. EDS spectrum of the SiO2–Cu catalyst (9.4 wt.% Cu).

9
0
P. Diz et al. / Applied Catalysis A: General 502 (2015) 86–95
Fig. 3. Entrapped Cu in the SiO2–Cu catalyst as a function of CuI loading.
Cu(II) at a field/[G] value of about 3.250 [Cu(I) is EPR-inactive] are
shown in Fig. 4. The majority of copper-catalyzed transformations
employ Cu(I) species and, inspired by Sharpless’s CuAAC proce-
dures [20], it was envisaged that treatment of this catalytic system
with a mild reducing agent would enable the reduction of the Cu(II)
to Cu(I) species. It was gratifying to verify that when the catalyst
was stirred with an aqueous solution of sodium ascorbate (0.5 M,
room temperature for 24 h) complete modification of its physical
appearance and EPR profile were observed. It can be seen in Fig. 4b
that, after ascorbate treatment, the pale blue colour had changed
to grey. Similarly, EPR experiments unequivocally demonstrated
that complete reduction of Cu(II) species occurred in both catalytic
systems irrespective of the copper source (CuI or CuSO ). The super-
4
imposed EPR spectra obtained for a representative catalyst of the
initial (blue powder) and final (grey powder) samples are shown in
Fig. 4c. These results suggest the presence of free copper(I) species
within the material.
3.2. Study of the catalytic activity
Once the synthesis of the SiO –Cu catalyst had been optimized
2
and it had been confirmed that copper was entrapped within the
matrix of the catalyst, the catalytic performance was evaluated in
two model copper-catalyzed reactions (CuAAC and Ullman reac-
tions). On the basis of the optimum copper entrapment results
(Fig. 3), it was decided to employ the catalyst that had a final copper
content of 9.4 wt.%.
3.3. Huisgen 1,3-dipolar cycloaddition (CuAAC)
The effectiveness of the SiO –Cu nanocatalyst in CuAAC was ini-
2
Fig. 4. (a) SiO2–Cu before treatment with sodium ascorbate. (b) SiO2–Cu after treat-
ment with sodium ascorbate. (c) EPR experiment showing the characteristic signal
of the paramagnetic Cu(II) state (top, corresponding to the sample before treatment)
and the Cu(I) showing the absence of a signal (bottom).
tially evaluated in two solvents (DMF and t-BuOH/H O) with two
2
organic azides (1a–b) and terminal acetylenes (2a–b), with DIPEA
employed as a base (Table 1). In these studies equimolar amounts
of the reactants were treated with SiO –Cu with different copper
2
loadings. The reaction mixtures were subjected to orbital stirring
◦
at 40 C for the required time (3–5 h) and the effect of the solvent
yields are the mean of at least two experiments in which freshly
prepared catalysts were used.
on the outcome of the reaction was investigated. The use of other
bases, such as TEA or potassium carbonate, did not improve the
yields. We were pleased to observe that simple mixing of commer-
cially available organic azides (1a–b) and acetylenes (2a–b) with
SiO –Cu (Table 1) led to smooth cycloaddition to afford the desired
,2,3-triazoles regardless of the modified parameters. The reported
A serious limitation for the widespread application of the
copper-mediated Huisgen cycloaddition in drug discovery pro-
grammes arises from the relatively low abundance of structurally
diverse collections of commercially available organic azides. In
addition, purification of the product is difficult when the reaction
2
1

P. Diz et al. / Applied Catalysis A: General 502 (2015) 86–95
91
Table 1
Representative 1,2,3-triazoles 3 obtained on employing the initial conditions.
N
SiO -Cu
N
2
R2
R1 N3
+
R2
N
DIPEA
R1
1
2
3
Entry
Compound
Substrate (1a–b)
Alkyne (2a–b)
Time (h)a,b
4a, 3b
Yield (%)a,b
90 , 91b
89 , 90b
83 , 98b
87 , 92b
a
1
2
3
4
3a
2
2
a
a
1a
1a
1b
1b
4a, 3b
5a, 4b
5a, 4b
a
3b
3c
3d
2b
a
a
2b
Conditions: acetylene derivative (1 mmol), organic azide (1 mmol), DIPEA (3 mmol), SiO2–Cu (0.05 mmol Cu), rt.
a
DMF as solvent.
t-BuOH/H2O (3:1) as solvent.
b
is incomplete and some alkyl azides decompose rapidly with the
risk of explosion upon distillation. Furthermore, alkyl azides gen-
erally have boiling points similar to those of the corresponding
alkyl bromides. Thus, we decided to initiate a systematic study
of the versatility of the nucleophilic substitution of the halide
using NaN [52–61] in t-BuOH/H O at room temperature (Table 2).
The initial exploration was aimed at the direct synthesis of 1,2,3-
triazoles 3 and the reaction of benzyl bromide, sodium azide and
phenylacetylene in the presence of TEA was chosen as a model
transformation. The procedure involved mixing equimolar quan-
evaluate the use of microwave heating. Finally, the best conditions
identified were as follows: 2-bromophenol (0.6 mmol), 2-chloro-N-
(4-methylphenyl)acetamide (0.5 mmol), SiO –Cu (100 mg, 14 mol%
2
◦
Cu) and Cs CO3 (1.0 mmol) in DMF (5.0 mL) under N2 at 100 C
2
under MW irradiation. The starting materials were consumed com-
pletely and the expected product 8a was obtained in 90% yield
after 1 h (Table 3, entry 1). A set of o-bromophenols and 2-chloro-
N-(aryl)acetamides were then selected for the synthesis of other
2H-1,4-benzoxazin-3-(4H)-ones (Table 3). A plausible pathway for
the formation of 2H-1,4-benzoxazin-3-(4H)-ones is proposed in
Table 3. The target compounds are formed in two steps. Firstly, in
3
2
tities of these reagents and the sol–gel material [SiO –Cu (5 mol%
2
Cu)] in t-BuOH/H O with vigorous stirring at room temperature
the presence of Cs CO , an intermolecular nucleophilic substitution
2
2 3
to give the corresponding 1,2,3-triazoles in good yields. Once the
reaction had finished, the catalytic system was removed by filtra-
tion and the product was extracted with diethyl ether and dried
under reduced pressure. These reaction conditions provided excel-
lent yields of triazoles 3 (Table 2) irrespective of the nature of the
alkyne and the alkyl bromide. A common feature of these experi-
ments was the absence of homocoupling byproducts (Table 2).
between o-bromophenol and the 2-chloroacetamide affords the
key ether intermediate 7 (Table 3). Indeed, the ether intermediate
7d was isolated during the reaction of 5b with 6b under conven-
tional heating (see supporting information). The efficiency of the
two-step transformation, which does not require any additional
ligand, demonstrates the catalytic performance and versatility of
the catalytic system reported here and highlights the favourable
environment provided by the polymeric matrix for the stabilization
of Cu(I) species.
3.4. Intramolecular Ullmann coupling reactions
Recent advances in copper-catalyzed reactions have stimu-
3.5. Recyclability
lated a plethora of novel improvements in Ullmann’s reaction
[
[
62–66], especially for copper-catalyzed Ullmann N-arylations
67–69,22,70]. In this context, one-pot Ullmann-based strategies
The recyclability of the supported catalyst was examined in
two representative transformations of each reaction studied (i.e.,
the Huisgen 1,3-dipolar cycloaddition and Ullmann intramolecular
coupling reaction). Firstly, it was verified that, after washing (with
water and diethyl ether) and drying under vacuum, the heteroge-
neous catalytic system recovered from the reaction could be reused
at least ten times in new reactions without a significant drop in
product yield (the average yields for the target structures are shown
in Table 4) and generate products with purities similar to those
obtained in the first run.
are particularly attractive as they enable the rapid and efficient
assembly of diverse heterocyclic compounds [71–76]. With the aim
of making a preliminary assessment of the usefulness of the novel
catalytic systems in a representative one-pot Ullmann reaction,
the reaction between 2-bromophenol (5a) and 2-chloro-N-(4-
methylphenyl)acetamide (6a) was studied. These model substrates
were submitted to classical Ullmann coupling conditions with diox-
ane or DMF as the solvent and conventional heating in a sealed tube
(
Cs CO were also used. In most cases the reaction was success-
ful (60–75% yield), but the long reaction times (24–48 h) and the
presence of the intermediate in the reaction mixtures led us to
◦
range of temperatures from 90 to 120 C). Variable equivalents of
In addition to its catalytic efficacy and recyclability, the
leaching of metal to the reaction media is a key issue to be
considered during the development of heterogeneous catalytic sys-
tems. We have taken into consideration the fact that the two
2
3

9
2
P. Diz et al. / Applied Catalysis A: General 502 (2015) 86–95
Table 2
Representative 1,2,3-triazoles obtained on employing the optimized conditions.
N
SiO -Cu
N
2
R2
R1
X
+
NaN3
+
R2
N
DIPEA
R1
4
2
3
Entry
Compound
Alkylating agent (4a–d)
Alkyne (2a–f)
Time (h)
4
Yield (%)
98
1
3a
2
a
4
4
a
a
2
3
4
5
3b
3d
3e
3f
4
6
3
6
89
83
87
85
2b
2b
4
4
b
4
c
c
2
b
2
b
c
6
7
3g
3h
3
3
88
92
4
2
d
4
d
2e
8
3i
3
80
4
a
2
f
Reaction conditions: acetylenic derivative (1 mmol), alkyl halide (1 mmol) and sodium azide (1 mmol), DIPEA (3 mmol), SiO2–Cu (0.05 mmol Cu) in 6 mL of t-BuOH/H2O (3:1),
rt. 3–6 h.
transformations evaluated in this study have quite different reac-
tion conditions (mechanism, temperature range and solvent). This
is particularly the case for oxidative addition, which occurs in the
Ullmann reaction and is a key factor in the leaching phenomenon.
In an effort to obtain evidence to support true heterogeneous
catalysis or to ascertain whether migration from the polymeric
matrix produces active homogeneous copper species, two addi-
tional experiments (hot filtration tests for the Huisgen CuAAC and
Ullmann reactions and a three-phase test) [77–81] were designed
SiO –Cu catalyst. Once the transformations had reached 50%
2
completion, the catalyst was removed from one of the reactions
by hot filtration of the solids through a preheated syringe and
the solids were then washed with hot solvent. After the solids
had been filtered off, the clear solution containing the filtrate
and the washings was allowed to react further in the absence of
solids. Comparison of the yields of the Huisgen products in the
reactions – both with and without solid catalyst – established
that filtration of the solids stopped the reaction. This suggests
that leaching of copper did not occur during the reaction. In
contrast, the reaction carried out without filtration proceeded
further to give 3a with a final conversion of 90%.
(Scheme 1).
3.6. Hot filtration test
(b) Ullmann
intramolecular
coupling
reaction:
Twin
One issue that must be addressed when using heterogeneous
experiments with 5-fluoro-bromophenol (5b), 2-chloro-
N-(4-ethoxyphenyl) acetamide (6b), potassium carbonate and
the SiO2–Cu catalyst in DMF were carried out for 20 min at
catalysts is metal leaching from the solid to the solution. With the
aim of obtaining information on this matter a hot filtration test was
performed for both reactions:
◦
100 C under MW heating. After this time, both transforma-
tions had reached approximately 50% conversion. The SiO –Cu
2
(
a) CuAAC: Twin CuAAC experiments using benzyl azide and
phenylacetylene in DMF were performed in the presence of the
catalyst was removed by filtration in one of the experiments.
Filtration was performed using a preheated hot syringe and the

P. Diz et al. / Applied Catalysis A: General 502 (2015) 86–95
93
Table 3
Proposed reaction pathway and structure of 2H-1,4-benzoxazin-3-(4H)-ones 8a–f.
a
Entry
1
Compound
o-Halophenol (5a–c)
Alkylating agent (6a–c)
Time (h)b
Yield (%)b
8a
1
90
87
5
a
6
a
2
8b
1
5
a
6
c
3
4
5
8c
8d
8e
1.5
80
83
89
5
a
6
b
1
5
b
6
b
1.5
5
5
c
c
6b
6
8f
1.5
88
6
c
a
◦
Reagents and conditions: 2-bromophenol 5a–c (0.6 mmol), 2-chloroamide 6a–c (0.5 mmol), SiO2–Cu (0.1 mmol Cu) and Cs2CO3 (1.0 mmol) in DMF (5.0 mL), 100 C, MW
heating, 1–1.5 h, under N2.
b
Isolated yield.
contents were transferred to another Kimble vial and 2 equiv.
of potassium carbonate were added. Heating was continued
in both reactions for 1 hour and the reactions were assessed
by TLC. It was found that the reaction without catalyst had
not progressed further to the final product 8d. Furthermore, a
greater amount of intermediate 7d (formed by intermolecular
nucleophilic substitution) was isolated in this reaction. By
3.7. Three-phase test
The immobilized catalyst was exposed to soluble reactants
and reagents bound to a solid support. If an active catalyst
leaches from the immobilized media it will result in conversion
of the resin-bound reagent. With this aim in mind, the supported
benzyl azide 10 was prepared (Scheme 1). Polystyrene-bound 4-
benzyloxybenzyl alcohol (1.25 mmol/g, Wang resin) was chosen
as the alternative support due to its rapid and efficient cleavage
contrast, in the other experiment (containing SiO –Cu the
2
catalyst) compound 8d was isolated in 83% yield.
Table 4
Number of cycles and average yields for representative reactions using SiO2–Cu.
Cycles/compound
1
2
3
4
5
6
7
8
9
10
Av. yield (%)
3a
3b
8a
8b
93
89
90
87
93
89
90
87
91
89
90
87
91
89
89
87
91
89
89
86
90
88
88
86
89
88
87
86
88
88
86
85
87
88
85
85
87
87
85
85
90
88
87
86

9
4
P. Diz et al. / Applied Catalysis A: General 502 (2015) 86–95
O
O
Cl
Cl
OH
O
DIEA/DCM
Cl
Wang resin
TMS-N3
TBAF
9
O
O
N3
10
1
)
1)
2
DIPEA
SiO -Cu(I)
DIPEA
CuI
(Not observed)
2
) TFA/ DCM
2
) TFA/ DCM
O
N
HO
N
N
11
Scheme 1. . Three-phase test performed for SiO2–Cu.
protocol. Firstly, 4-(chloromethyl)benzoyl chloride was tethered
to Wang resin under basic conditions and the resulting material
was subsequently incubated with trimethylsilyl azide and TBAF
silica matrix is 9.4 wt.%. Given the current interest in reusable cop-
per nanoparticles and the scarcity of reusable and versatile solid
catalysts for a range of reactions, the copper-supported catalyst
presented here constitutes a step forward in the development of
highly active, heterogeneous and reusable catalysts.
(
Scheme 1) to generate the polymer-bound reactive 1,3-dipolar
compound 10. The immobilized azide 10 was then subjected to
,3-dipolar cycloaddition (Scheme 1) using phenylacetylene (2a)
as the dipolarophile along with one of the catalysts described
1
Acknowledgment
here [SiO –Cu(I), copper loading: 9.4%]. In a parallel experiment,
2
the supported azide 10 and 2a were reacted in the presence of
DIPEA and copper(I) iodide (Scheme 1). After 24 h at room tem-
perature, complete conversion of 2a was observed with only the
latter experiment affording (after appropriate work-up and cleav-
age) 4-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]benzoic acid (11).
These findings are consistent with the results obtained during the
determination of copper in two representative 1,2,3-triazoles in the
series (compounds 3a and 3b). Inductively coupled plasma mass
spectroscopy (ICP-MS) analysis did not show the presence of cop-
per traces in the 1,2,3-triazoles 3a and 3b (see experimental part).
These findings unequivocally confirm that soluble copper species
are not involved in the catalytic cycle of the Huisgen 1,3-dipolar
This work was financially supported by the Galician Govern-
ment (Spain, Projects: 07TMT001CT and GPC-2014-PG037).
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.apcata.2015.05.
0
25
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