A comparative study between Cu(INA)2-MOF and [Cu(INA)2(H2O)4] complex for a click reaction and the Biginelli reaction under solvent-free conditions

Article abstract of DOI:10.1039/c9ra10171c

The catalytic activity of metal-organic framework Cu(INA)₂ (INA = isonicotinate ion) and the complex [Cu(INA)₂(H₂O)₄] were studied in the Copper-catalyzed Azide-Alkyne Cycloaddition (CuAAC) and Biginelli reactio

Full text of DOI:10.1039/c9ra10171c

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A comparative study between Cu(INA)2-MOF and
[Cu(INA)2(H2O)4] complex for a click reaction and
the Biginelli reaction under solvent-free
conditions†
Cite this: RSC Adv., 2020, 10, 3407
Julia C. Mansano Willig,a Gustavo Granetto,a Danielly Reginato,a Felipe R. Dutra,a
c
E´rica Fernanda Poruczinski,a Isadora M. de Oliveira,b Helio A. Stefani,
Sılvia D. de
´
Campos,a E´lvio A. de Campos,a Flavia Manarina and Giancarlo V. Botteselle
´
a
*
The catalytic activity of metal–organic framework Cu(INA)2 (INA ¼ isonicotinate ion) and the complex
[Cu(INA)2(H2O)4] were studied in the Copper-catalyzed Azide–Alkyne Cycloaddition (CuAAC) and
Biginelli reaction under solvent-free reaction conditions. The robust, efficient and eco-friendly new
method allowed the preparation of a variety of 1,2,3-triazole compounds in good to excellent yields and
high selectivity for the 1,4-disubstituted triazole. Moreover, for the Biginelli reaction between aldehydes,
ethyl acetoacetate and urea, the corresponding dihydropyrimidinones (DHPMs) were also obtained in
satisfactory yields under mild reaction conditions for both catalysts. The comparative study between
Cu(INA)2-MOF and [Cu(INA)2(H2O)4] complex demonstrated better results for the Cu-MOF, for both the
yields and the regioselectivity of the products. Furthermore, no change in the heterogeneous catalyst
structure was observed after the reaction, allowing them to be recovered and reused without any loss of
activity.
Received 4th December 2019
Accepted 9th January 2020
DOI: 10.1039/c9ra10171c
rsc.li/rsc-advances
separation, and drug delivery, and they exhibit optical and
magnetic properties.5
Introduction
Among the MOFs used in heterogeneous catalysis, the copper
metal–organic framework (Cu-MOF) has emerged as a potent and
useful catalyst in several transformations as a result of the
abundance, low toxicity and low cost of copper and because of the
presence of a coordinatively unsaturated metal centre in its
structure.6 For instance, Phan, Troung and co-workers have used
Cu(INA)2-MOF (INA ¼ isonicotinate ion) as a heterogeneous
catalyst for the N-arylation of several heterocycles in excellent
yields.7 More recently, the same research group reported the
nucleophilic triuoromethylation of aromatic boronic acids by
using the same efficient Cu(INA)2-MOF catalyst.8
Depending on reaction conditions, the combination of Cu(II) and
isonicotinate anion can produce two structures: the Cu(INA)2-
MOF9,10 or the complex [Cu(INA)2(H2O)4].11,12 The difference between
the copper catalytic centres of these structures is shown in Fig. 1.
Despite the fact that these compounds are prepared by distinct
methods, the hydrolysis of Cu(INA)2-MOF affords [Cu(INA)2(H2O)4],
which is reverted to the MOF by thermal treatment.13
Coordination polymers of metal–organic frameworks (MOFs)
have been gaining considerable attention in recent years in the
eld of catalysis. They have specic properties, such as porosity,
high surface area, high thermal stability and high crystallinity,
which make them potential catalysts in several organic reac-
tions.1 These properties are possible due to the auto-
organisation system of the MOFs, generated by the careful
combination of a metallic centre and organic ligands, allowing
the formation of a porous coordination polymer structure that
may be either 2-dimensional or 3-dimensional.2 Moreover,
these specic properties combined with the low solubility of
MOFs permit their wide application as heterogeneous cata-
lysts.3 This also facilitates the recovery and reuse of MOFs,
which can be characterised as green and recyclable catalysts.4 In
addition, other important applications of MOFs are gas storage,
a
ˆ
Centro de Engenharias e Ciencias Exatas-CECE, Universidade Estadual do Oeste do
´
Parana, Toledo, 85903-000, PR, Brazil. E-mail: giancarlo.botteselle@unioeste.br;
Aware of the effectiveness of Cu(INA)2-MOF in the organic
reactions cited above, we decided to extend the use of this
catalyst to the Copper-Catalysed Azide–Alkyne Cycloaddition
(CuAAC) and Biginelli reactions, performing a comparative
study of its catalytic activity with the [Cu(INA)2(H2O)4] complex.
It is noteworthy that some MOFs have recently been used as
gian.botteselle@gmail.com
b
´
´
˜
Departamento de Quımica Fundamental, Instituto de Quımica, Universidade de Sao
˜
Paulo, Sao Paulo, Brazil
c
´
ˆ
ˆ
Departamento de Farmacia, Faculdade de Ciencias Farmaceuticas, Universidade de
˜
˜
Sao Paulo, Sao Paulo, 05508-000, SP, Brazil
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra10171c
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catalysts for both of these kinds of reactions, affording the High-resolution exact mass measurements were performed
synthesis of corresponding 1,2,3-triazoles and dihydropyr- using atmospheric-pressure chemical ionisation (APCI), posi-
imidinones (DHPMs), respectively.14,15 Both of these heterocy- tive mode, on a Bruker Daltonics micrOTOF-Q II mass spec-
clic compounds have been widely studied as building blocks for trometer and electrospray ionization 10 (ESI), positive mode, on
the synthesis of biologically active compounds with important a quadrupole time-of-ight (TOF) Agilent QTOF-MS spectrom-
pharmacological properties.16,17 For example, triazoles and eter. The thermogravimetric analyses (TGA) were performed on
DHPMs containing an organoselenium unit (synthesised by a PerkinElmer STA 6000 in a nitrogen atmosphere owing at 10
molecular hybridisation strategy) have attracted considerable mL minꢀ1, with a heating rate of 50 ꢁC minꢀ1 from 25 ꢁC to
attention as potential multi-targeted anticancer or anti-Alz- 900 ꢁC. The X-ray diffraction (XRD) analyses were performed on
heimer's actives.18
a Bruker D2 Phaser Diffractometer equipped with CuKa radia-
˚
Thus, in connection with our interests in the application of tion (l ¼ 1.5418 A). The diffraction patterns were obtained at
MOFs in catalysis19 and in the development of sustainable angles between 10ꢁ and 80ꢁ (q–2q).
chemical protocols,20 herein we describe the straightforward
methods for the click (CuAAC) and Biginelli multicomponent
Cu(INA)2-MOF synthesis
reactions, employing Cu(INA)2-MOF and the [Cu(INA)2(H2O)4]
This MOF was synthesised using a slightly altered synthesis
complex as catalysts, under solvent-free conditions. We found
route based on a method reported previously.10 A mortar and
pestle were used to grind a mixture of Cu(OAc)2$H2O (0.5 g, 2.5
mmol) and isonicotinic acid (0.5 g, 4 mmol) without solvent.
that the click reaction was fast and selective for the synthesis of
1,4-disubstituted-1,2,3-triazoles, including the synthesis of tri-
azoles containing a selenium atom. Besides this, the reuse of
The formation of the reaction product was indicated by the
the catalyst was shown to be possible.
characteristic odour of acetic acid, released as a by-product.
Aer this, the mixture was transferred to a beaker and was
allowed to react for 24 h. The desired product still contained
some water and acetic acid, so it was heated to 200 ꢁC for 4 h to
Experimental
Materials and methods
remove the by-products, to give the crystalline and porous
framework in quantitative yield. The XRD analysis used to
conrm the identity of Cu-MOF is found in Fig. 3. For IR and
TGA analysis, see ESI.†
All reagents and solvents were commercially available and used
without any further purication. Thin-layer chromatography
(TLC) was performed using Merck Silica Gel GF254, 0.25 mm
thickness. Flash column chromatography was performed using
Merck Silica Gel 60 (230–400 mesh). Melting points were
[Cu(INA)2(H2O)4]-complex synthesis
measured on a Fisatom 430 D. All compounds were charac-
1
terised by H NMR and 13C NMR; the spectra can be found in
The complex of Cu(INA)2 was obtained according to literature
procedure.12 For the XRD, IR and TGA analyses used to conrm
the identity of the compound, see ESI.†
the ESI.† The spectra were obtained using a Bruker DPX 300 (1H
at 300 MHz and 13C at 75 MHz), using CDCl3 and DMSO-d6 as
1
solvents. All H NMR shis are reported in d units, parts per
million (ppm), and were measured relative to the signal for TMS
(0.00 ppm). Data are reported as follows: chemical shi (d),
multiplicity, coupling constant (J) in hertz and integrated
intensity. Abbreviations to denote the multiplicity of a partic-
ular signal are as follows: s (singlet), d (doublet), t (triplet), q
(quartet) and m (multiplet). All 13C NMR shis are reported
in ppm relative to deuterated-chloroform (77.23 ppm), unless
otherwise stated, and all spectra were obtained with 1H
decoupling. High-resolution mass spectra (HRMS) were recor-
ded on a Shimadzu LCMS-IT-TOF ESI-TOF mass spectrometer.
Table 1 Optimisation of click reactiona
Entry Catalyst (mol%)
Time
T (ꢁC) Yieldb (%)
1
2
3
4
5
6
7
8
[Cu(INA)2(H2O)4]complex (10.0) 10 min 80
[Cu(INA)2(H2O)4] complex (5.0) 8 min 80
[Cu(INA)2(H2O)4] complex (1.0) 12 min 80
[Cu(INA)2(H2O)4] complex (0.5) 20 min 80
75
92
93
80
35
30
98
95
50
70
65
20c
[Cu(INA)2(H2O)4] complex (1.0) 4 h
[Cu(INA)2(H2O)4] complex (1.0) 24 h
50
r.t.
80
80
Cu(INA)2-MOF (5.0)
Cu(INA)2-MOF (1.0)
Cu(INA)2-MOF (1.0)
Cu(INA)2-MOF (0.5)
Cu(INA)2-MOF (1.0)
—
2 min
4 min
15 min 50
10 min 80
18 h
6 h
9
10
11
12
r.t.
80
a
Fig. 1 The copper catalytic centre of the Cu(INA)2-MOF (left, adapted
from ref. 10b) and [Cu(INA)2(H2O)4] complex (right, adapted from ref.
11). Cu; O; N; C.
Reaction conditions: benzyl azide (0.5 mmol), phenylacetylene (0.5
mmol). b Isolated yield. c Mixture of regioisomers.
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Table 2 Synthesis of Cu-MOF-catalysed 1,4-disubstituted-1,2,3-triazole derivativesa
[Cu(INA)2(H2O)4]-
complex
Cu(INA)2-MOF
Entry
1
R1
R2
Product
Time
Yieldb (%)
Time (h)
Yieldb (%)
PhCH2, 1a
Ph, 2a
12 min
93
85
4 min
95
2
3
4
5
6
1a
4-OMeC6H4, 2b
4-MeC6H4, 2c
1-Naphthyl, 2d
4-NH2C6H4, 2e
2a
5 min
6 min
1 h
4 min
5 min
1 h
90
90
95
96
92
1a
81
97
70
86
1a
1a
10 min
10 min
10 min
10 min
4-OMeC6H4, 1b
7
8
1b
1b
2e
2c
40 min
70
40 min
1 h
90
95
—
—
9
1a
1a
PhCH2Se, 2f
PhSe, 2g
2 h
80
2 h
86
98
10
1.5 h
96c
1.5 h
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Table 2 (Contd.)
[Cu(INA)2(H2O)4]-
complex
Cu(INA)2-MOF
Entry
R1
R2
Product
Time
Yieldb (%)
Time (h)
Yieldb (%)
11
1a
PhSeCH2, 2h
12 h
50
12 h
70
a
b
c
Reaction conditions: azide (0.5 mmol), acetylene (0.5 mmol), catalyst (1 mol%). Isolated yield. A mixture of 1 : 1.4 ratio of the 1,4- and 1,5-
regioisomers determined by 1H NMR spectroscopy.
catalyst was reused in subsequent reactions under solvent-free
conditions, at 80 C.
General procedure for the click reaction
ꢁ
In a 10 mL tube, benzyl azide or 4-azidoanisole (0.5 mmol), one
of the acetylenes (0.5 mmol) and Cu(INA)2-MOF or [Cu(INA)2(-
H2O)4] complex (1 mg) were added and stirred at 80 C for the
time indicated in Table 2. The reaction was monitored by thin
layer chromatography (TLC) to determine reaction time. The
organic compounds were solubilised in dichloromethane,
separated by centrifugation and concentrated under vacuum.
For compounds 3f–k (Table 2) catalysed by Cu-complex, the
crude product was puried by ash column chromatography
For metal leaching test the Inductively Coupled Plasma
Optical Emission Spectrometer (ICP-OES) measurements were
performed on a PerkinElmer Optima 7000 DV ICP-OES. The
calibration curve was performed from copper concentrations of
1, 5, 10, 20 and 30 ppm, which obtained an r2 of 0.9999169. The
sample was prepared by digestion of the organic matter with hot
sulphuric acid and some drops of nitric acid.
ꢁ
through silica gel, using an appropriate mixture of hexane and Results and discussion
ethyl acetate as the eluent. The identity and purity of the
Catalytic studies of Cu(INA)2-MOF and [Cu(INA)2(H2O)4]
complex in the synthesis of a 1,2,3-triazole
products were conrmed by 1H NMR, 13C NMR and melting
points, and all spectral data were in perfect agreement with
those reported in the literature (see ESI†).
Initially, we focused our attention on the optimisation of the
reaction conditions using benzyl azide (1a) and phenylacetylene
(2a) as model substrates catalysed by Cu(INA)2-MOF or by
[Cu(INA)2(H2O)4] complex (Table 1). The reaction time was
determined by consumption of the starting materials (TLC
analysis) or by the product precipitation. At rst, the catalyst
loading in the reaction system was evaluated. Initially, the
reaction was performed with 10 mol% of [Cu(INA)2(H2O)4]
complex, and the desired product 3a was obtained in 75% yield
(Table 1, entry 1).
When the amount of the catalysts was decreased to 5 mol%,
the yield increased signicantly to 92 and 98% (Table 1, entries
2 and 7, respectively). Notably when 1 mol% of [Cu(INA)2(H2O)4]
complex or Cu(INA)2-MOF was used, no signicant change in
the yield was observed, once the reaction is performed in
solvent free conditions, a greater amount of solid impairs sol-
ubilisation under continuous stirring, thus even with a lower
catalyst load the yield remains, furnishing the desired triazole
General procedure for the Biginelli reaction
An aldehyde (0.5 mmol), urea (0.6 mmol), ethyl acetoacetate (1
mmol) and cꢁatalyst (10 mg) were placed in a 10 mL tube and
stirred at 80 C for the time indicated in Table 4. The organic
compounds were then extracted with ethyl acetate (3 ꢂ 10 mL),
ltered and concentrated under vacuum. The crude product
was puried by ash column chromatography through silica
gel, using an appropriate mixture of hexane and ethyl acetate as
the eluent. The identity and purity of the products were
conrmed by 1H NMR and 13C NMR, and all spectral data were
in perfect agreement with those reported in the literature (see
ESI†).
Recycling of the catalysts and leaching test
The recyclability of the catalysts was investigated. Aer 3a in 93% and 95% yield, respectively (Table 1, entries 3 and 8).
complete separation of the organic phase of the reaction by However, further decreasing the amount of catalyst provided
centrifugation, the catalysts were washed with dichloromethane the product in lower yield in both cases (Table 1, entries 4 and
and then dried in an oven at 100 ꢁC for 1 h. The dried solid 10).
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Focusing on the inuence of the temperature on the reac- [Cu(INA)2(H2O)4] complex was used, the products 3f–k required
tion, we discovered it had a great inuence on the yield values. a simple purication by column.
Thus, when the reaction was carried out at 50 ꢁC, using
Moreover, in order to investigate the synthetic utility of our
[Cu(INA)2(H2O)4] complex for 4 h and Cu(INA)2-MOF for 15 min, methodology, we evaluated whether the reaction could be per-
the yield decreased to 35 and 50%, respectively (Table 1, entries formed at the gram scale under the optimised conditions
5 and 9). Moreover, a signicant decrease in the yield and longer (Scheme 1). Fortunately, the corresponding product 3a was
reaction time was observed when the reaction was carried out at obtained in 95% yield using Cu(INA)2-MOF as catalyst and 90%
room temperature (Table 1, entries 6 and 11).
using [Cu(INA)2(H2O)4] complex as catalyst, which is very
It is important to note that, in the absence of catalyst, the important in organic synthesis, indicating that this method-
reaction was not effective, and a mixture of 1,4- and 1,5- ology can be used to prepare 1,4-disubstituted-1,2,3-triazoles on
regioisomers of 1,2,3-triazoles was observed (Table 1, entry 12). a larger scale.
This emphasises the activity and regioselectivity of Cu-MOF and
Cu-complex in this kind of transformation.
Having established the best reaction conditions, we evalu-
ated the scope of the protocol for both catalysts by using
a variety of substrates identied in Table 2.
Catalytic studies of Cu(INA)2-MOF and [Cu(INA)2(H2O)4]
complex in the Biginelli reaction
For the purpose of optimising our protocol, we used benzalde-
hyde (4a), urea (5) and ethyl acetoacetate (6) as common
substrates. Evaluated were some parameters such as catalyst
loading, temperature, reaction time and solvent (Table 3). The
one-pot procedure was initially studied by using 10 mol%ꢁ of
[Cu(INA)2(H2O)4] complex in solvent-free conditions at 100 C,
affording the desired dihydropyrimidinone (DHPM) 7a in 90%
yield (Table 3, entry 1). However, on decreasing the temperature
to 80 ꢁC, no signicant difference in the yield was observed
(Table 3, entry 2). On the order hand, when the reaction was
We explored the reaction of different aromatic acetylenes 2a–
e with benzyl azide (1a), and no signicant difference in reac-
tivity was observed whether electron-withdrawing or electron-
donating groups were attached to the aromatic ring, affording
the desired 1,2,3-triazoles 3a–e in excellent yields and short
reaction times (Table 2, entries 1–5). It is worth noting that the
Cu(INA)2-MOF provided better results than the complex.
In addition, when the 4-azidoanisole (1b) was used as
substrate in the presence of phenylacetylene (2a) and 4-ethy-
nylaniline (2d), the corresponding products 3f and 3g were
obtained in 86 and 70% yield, respectively, for [Cu(INA)2(H2O)4]
complex. On the other hand, when Cu(INA)2-MOF was used as
catalyst, the same products 3f and 3g were obtained in 92 and
90% yields, respectively (Table 2, entries 6 and 7). Furthermore,
the product 3h was only synthesised in the presence of Cu-MOF
(Table 2, entry 8).
ꢁ
performed at 50 C, the product 7a was obtained in only 25%
yield (Table 3, entry 3). Moreover, at room temperature the
product was not obtained, and all starting material was recov-
ered; this shows that temperature inuences the reaction (Table
3, entry 4). In addition, when the reaction time was reduced
from 2.5 to 2 h at 80 ꢁC, no signicant change in the yield was
observed (Table 3, entry 5).
Because of the important biological activity of triazoles
containing an organoselenium unit,14 we decided to extend this
reaction system to acetylenes containing the selenium atom, 2f–
h. Thus, it was possible to synthesise the compounds 3i–k in
satisfactory yields (50–98%) with both catalysts (Table 2, entries
9–11). However, the product 3j was obtained in an approxi-
mately 1 : 1.4 ratio of the 1,4- and 1,5-regioisomers under Cu-
complex catalysis, whereas the reaction was regioselective
(1,4-substituted triazole only) when catalysed by the Cu-MOF
(Table 2, entry 10). It is worth mentioning that, the product 3i
appears to have been synthesised herein for the rst time in the
literature.
To evaluate the catalyst loading, we carried out the reaction
with 5 mol% of [Cu(INA)2(H2O)4] complex, and the yield of the
desired product was reduced to 60% (Table 3, entry 7). It is
Table 3 Optimisation of Biginelli reactiona
It is remarkable that all products of the reactions with
Cu(INA)2-MOF could be simply extracted with dichloromethane
and separated by centrifugation without the necessity of puri-
cation by chromatographic column. However, when the
#
Cu(INA)2 (mol%)
Time (h)
T (ꢁC)
Yieldb (%)
1
2
3
4
5
6
7
8
9
[Cu(INA)2(H2O)4] complex (10)
[Cu(INA)2(H2O)4] complex (10)
[Cu(INA)2(H2O)4] complex (10)
[Cu(INA)2(H2O)4] complex (10)
[Cu(INA)2(H2O)4] complex (10)
[Cu(INA)2(H2O)4] complex (10)
[Cu(INA)2(H2O)4] complex (5)
—
2.5
2.5
2.5
2.5
2.0
1.5
2.0
2.0
2.0
100
80
50
r.t.
80
80
80
80
80
90
88
25
—
90
80
60
35
99
Cu(INA)2-MOF (10)
a
Reaction conditions: urea (0.6 mmol), benzaldehyde (0.5 mmol), ethyl
acetoacetate (1.0 mmol) and Cu(INA)2 (10 mol%). b Isolated yield.
Scheme 1 Scale-up of the reaction.
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Table 4 Synthesis of DHPM derivatives under Cu(INA)2 catalysisa
[Cu(INA)2(H2O)4] complex
Cu(INA)2-MOF
Time (h)
Entry
R
Product
Time (h)
Yieldb (%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
C6H5, 4a
7a
7b
7c
7d
7e
7f
7g
7h
7i
2.0
2.5
2.5
2.5
2.0
2.0
1.0
2.5
24.0
90
71
80
44
50
50
82
68
25
2.0
2.5
2.5
2.5
2.0
2.0
1.0
2.5
24.0
99
80
82
55
55
55
85
72
33
4-OMeC6H4, 4b
2-OMeC6H4, 4c
3,4,5-OMeC6H2, 4d
4-MeC6H4, 4e
3-OH-C6H4, 4f
2-NO2C6H4, 4g
2-Pyridine, 4h
2-Naphthyl, 4i
a
b
Reaction conditions: aldehyde (0.5 mmol), urea (0.6 mmol), ethyl acetoacetate (1.0 mmol) and catalyst (10 mol%). Isolated yield.
notable that, in the absence of the catalyst, the DHPM 7a was less sterically hindered in the MOF structure because the
obtained in only 35% yield (Table 3, entry 8).
geometry is distorted square pyramidal, while in the complex it
Aiming to determine the effect of the MOF in the Biginelli is octahedral (Fig. 1). Moreover, for the cycloaddition reaction,
reaction, we extended our Cu-complex protocol in Table 3, entry a catalyst–substrate bond is necessary, and for this to occur, at
5, by substituting Cu(INA)2-MOF as catalyst. As a result, the least one of the water molecules coordinated to the metal must
product 7a was obtained in almost quantitative yield (Table 3, be removed in the case of the complex.
entry 9). Next, we explored the generality of this protocol for
both catalysts, performing a comparative study between cata-
lytic activity of the [Cu(INA)2(H2O)4] complex and of the
Recyclability
Cu(INA)2-MOF in the Biginelli reaction (Table 4).
In order to evaluate the recyclability of the catalysts, we recov-
ered the [Cu(INA)2(H2O)4]-complex and the Cu(INA)2-MOF and
reused them in subsequent reactions between benzyl azide (1a)
and phenylacetylene (2a) (Fig. 2). So, aer the reaction was
nished, the product 3a was solubilised with dichloromethane
and separated by centrifugation. Aer isolation of the liquid
Firstly, the reaction was conducted with several aldehydes,
using the optimal reaction conditions catalysed by [Cu(INA)2(-
H2O)4] complex. For example, when the reaction was performed
using different electron-donating groups attached to the
aromatic ring, such as 4-methoxy, 2-methoxy, 3,4,5-trimethoxy,
4-methyl and 3-hydroxy substituents, which decrease the alde-
hyde reactivity, the corresponding DHPMs 7b–f were obtained
in 44–80% yields (Table 4, entries 2–6).
On the other hand, when we used aldehydes containing
electron-withdrawing groups, such as ortho-nitrobenzaldehyde
(4g), the desired product 7g was obtained in 82% yield (Table 4,
entry 7). Moreover, it was possible to synthesise a DHPM
compound 7h containing a heterocyclic unit from 2-pyr-
idinecarboxaldehyde (4h) in 68% yield (Table 4, entry 8).
Subsequently, the use of naphthaldehyde (4i) afforded the cor-
responding product 7i in 25% yield; this low yield could be
associated with hindrance due to the bulky and rigid naphthyl
group (Table 4, entry 9).
The same aldehydes 4a–i were used for the Biginelli reaction
catalysed by Cu(INA)2-MOF, and in all cases the DHPMs 7a–i
were obtained in better yields compared to Cu-complex (Table 4,
entries 1–9).
Thus, according to the reactivity of Cu-(INA)2-MOF compared
with the Cu-complex, some points can be noted regarding the
structures of these compounds. The copper catalytic centre is
Fig. 2 Catalyst reuse.
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A plausible mechanism for click reaction
On the basis of the work of Luz et al.,21 which did not found
evidence of Cu(I) species generated during Cu-MOF catalysed
1,3-dipolar cycloaddition reaction, it was proposed that the
active species for the click reaction with Cu-MOF consist of
Cu(II) active sites. Thus, in accordance with previous reports,21,22
a
plausible reaction pathway for the synthesis of 1,4-
disubstituted-1,2,3-triazoles is illustrated in Scheme 2.
In this pathway the catalytic cycle begins with the copper
coordination to the alkyne (I), which increases the acidity of
terminal alkyne, affording the formation of copper acetylide (II).
Subsequently, this species reacts with organic azide, via 1,3-
dipolar cycloaddition, to afford the triazolyl-copper species (III).
Lastly, the desired triazole (IV) is obtained through protonation
of intermediate III, followed by catalyst regeneration.
Fig. 3 XRD analysis of Cu(INA)2-MOF before and after five catalytic
cycles.
Conclusions
organic phase and evaporation of the solvent, the catalysts were We report herein the catalytic activity of Cu(INA)2-MOF in the
reused directly, without any further treatment. The recovered Copper-Catalysed Azide–Alkyne Cycloaddition (CuAAC) and
catalysts were then used for ve more reaction cycles each, Biginelli reactions and the comparative study with its analogous
without a signicant decrease in the yield of product 3a.
However, the Cu(INA)2-MOF produced a better result in allowed the preparation of 1,2,3-triazoles and dihydropyr-
catalyst reuse, as shown in Fig. 2.
imidinones (DHPMs) under solvent-free conditions. Remark-
complex [Cu(INA)2(H2O)4]. The straightforward methodologies
The crystal structure of Cu(INA)2-MOF remained unchanged ably, the Cu-MOF was found to be a more highly efficient
aer ve catalytic cycles, as shown in the X-ray diffraction catalyst than the Cu-complex for these reactions, affording the
patterns in Fig. 3.
desired products in very high yields and producing selectively
the 1,4-disubstituted-1,2,3-triazoles. These MOF-catalysed
reactions showed advantages that include the use of a recy-
clable catalyst, ease of scale-up to gram scale, atom-economy,
short reaction time, absence of base and reducing agents and
a solvent-free approach. Indeed, all these features make this
a green alternative for easy access to 1,4-disubstituted-1,2,3-
triazoles and DHPMs.
Leaching test
The heterogeneity of CuAAC reaction was investigated by the
leaching test, where the amount of copper was determined by
ICP-OES analysis of the solid obtained aer the reaction. Thus,
the catalyst was ltered with dichloromethane (using a poly-
propylene syringe lter) and the solvent was evaporated under
reduced pressure. Aer this, digestion of the organic sample
was performed and analysed by ICP-OES. The analysis indicates
that there are no traces of leached copper into the sample.
Conflicts of interest
The authors declare no conict of interest.
Acknowledgements
The authors gratefully thank Araucaria Foundation for
a fellowship to FGM (FAAP-Unioeste 003/2017) and The
National Council Scientic and Technological Development for
nancial support (CNPQ-429831/2018-8).
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