Bridging homogeneous and heterogeneous catalysis with MOFs: Cu-MOFs as solid catalysts for three-component coupling and cyclization reactions for the synthesis of propargylamines, indoles and imidazopyridines

Article abstract of DOI:10.1016/j.jcat.2011.10.001

Copper-containing MOFs are found to be active, stable and reusable solid catalysts for three-component couplings of amines, aldehydes and alkynes to form the corresponding propargylamines. Two tandem reactions, including an additional cyclization step, le

Full text of DOI:10.1016/j.jcat.2011.10.001

Journal of Catalysis 285 (2012) 285–291
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Bridging homogeneous and heterogeneous catalysis with MOFs: Cu-MOFs as
solid catalysts for three-component coupling and cyclization reactions for the
synthesis of propargylamines, indoles and imidazopyridines
⇑
⇑
I. Luz, F.X. Llabrés i Xamena , A. Corma
Instituto de Tecnología Química UPV-CSIC, Universidad Politécnica de Valencia, Consejo Superior de Investigaciones Científicas, Avda. de los Naranjos s/n, 46022 Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Copper-containing MOFs are found to be active, stable and reusable solid catalysts for three-component
couplings of amines, aldehydes and alkynes to form the corresponding propargylamines. Two tandem
reactions, including an additional cyclization step, leads to the effective production of indoles and imi-
dazopyridines. In particular, the lamellar compound [Cu(BDC)] (BDC = benzene dicarboxylate) is highly
efficient for the preparation of imidazopyridines, although a progressive structural change of the solid
to a catalytically inactive compact structure is produced, causing deactivation of the catalyst. Neverthe-
less, the phase change can be reverted by refluxing in DMF, which recovers the original lamellar structure
and the catalytic activity of the fresh material. The use of [Cu(BDC)] for this reaction also prevents the
formation of Glaser/Hay condensation products of the alkyne, even when the reaction is performed in
air atmosphere. This is a further advantage of [Cu(BDC)] with respect to other homogeneous copper
catalysts, for which the use of an inert atmosphere is necessary.
Received 10 August 2011
Revised 4 October 2011
Accepted 4 October 2011
Available online 10 November 2011
Keywords:
Cu-MOF catalysis
Three-component coupling
Indole
Imidazopyridine
Ó 2011 Elsevier Inc. All rights reserved.
1. Introduction
We have recently reported on the catalytic application of me-
tal–organic frameworks featuring Cu2+ ions coordinated to four N
Transition metal complexes are successful homogeneous cata-
lysts with well defined single active sites. Their heterogeneization
allows having solid recyclable molecular catalysts with well
defined and predesigned active centers. In this sense much effort
has been done to develop adequate supports and heterogeneiza-
tion procedures that allow, not only preserving the catalytic char-
acteristics of the starting homogeneous catalyst but, sometimes,
even improving their behavior by a cooperative effect between
the transition metal complex and the support [1]. Other possibili-
ties to transform homogeneous catalysts based on transition metal
complexes into solid heterogeneous catalysts involve the synthesis
of hybrid organic–inorganic structured porous materials [2,3] and
the preparation of coordination polymers [4–7]. One type of
coordination polymers are the so-called metal–organic frame-
works (MOFs) in where metal nodes are connected by organic link-
ers through strong coordination bonds in a tridimensional net,
forming crystalline, hybrid microporous materials. It appears then
that by properly selecting the metal and the organic linkers it
should be possible to obtain an heterogeneous counterpart of some
homogeneous catalysts.
atoms belonging to heterocyclic rings, thus forming CuN4 centers.
Examples of such materials are [Cu(2-pymo)2] and [Cu(im)2]
(2-pymo = 2-hydroxypyrimidinolate; im = imidazolate) [8,9]. In
these compounds, each heterocycle (pyrimidine or imidazole) is
coordinated to two Cu2+ ions, leading in both cases to a neutral
and highly flexible 3D distorted sodalite-type framework [10].
We have recently found that the coordination and electronic prop-
erties of the Cu2+ ions in these MOFs are analogous to those of
N-heterocyclic copper coordination complexes [11,12]. Moreover,
the high flexibility of the framework allows copper ions to coordi-
nate to adsorbed molecules, either by expanding the coordination
sphere of copper ions or by displacing one heterocyclic ligand,
without causing structure collapse. Therefore, given the similari-
ties between the copper sites in the above described MOFs, and
the N-heterocyclic copper coordination complexes, it is not
surprising that both [Cu(2-pymo)2] and [Cu(im)2] could be hetero-
geneous active catalysts for reactions that occur in the presence of
those copper complexes. Indeed, we have seen this similarity for
the liquid phase allylic oxidation of a number of substrates [11],
as well as for the 1,3-dipolar cycloaddition of azides to alkynes
(‘‘click’’ reaction) [12], which involves the formation of a copper-
acetylide intermediate. In this sense, [Cu(2-pymo)2] and [Cu(im)2]
represent heterogeneous counterparts of the versatile and exten-
sively used homogeneous Cu2+ coordination complexes containing
⇑
Corresponding authors. Fax: +34 963877809.
E-mail addresses: fllabres@itq.upv.es (F.X. Llabrés i Xamena), acorma@itq.upv.es
(A. Corma).
0021-9517/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2011.10.001

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I. Luz et al. / Journal of Catalysis 285 (2012) 285–291
N-heterocyclic ligands. Following this idea, in the present work, we
have studied a more complex reaction such as the one-pot three-
component coupling reaction between alkynes, aldehydes and
amines, as a means to prepare the corresponding propargylamines
with a series of copper-containing MOFs as catalysts. The interest
of this reaction lies on the versatility of propargylamines as
synthetic intermediates in organic synthesis and as important
structural elements in natural products and therapeutic drug mol-
ecules [13,14]. Given the recognized catalytic activity of copper N-
heterocyclic coordination complexes for this reaction, we have
anticipated that these homogeneous catalysts could be replaced
by Cu-MOFs as heterogeneous alternatives. We have examined
the scope of the reaction and the various conditions in which the
reaction can proceed, and good yields have been obtained without
altering the crystalline structure of the materials. We have also
prepared indole derivatives in good yield, by a tandem one-pot
three-component coupling reaction followed by a 5-endo-dig cycli-
zation. Following a similar reaction scheme, the imidazopyridine
nucleus, analogous to that found in a family of anxiolytic drugs,
such as alpidem or zolpidem, has also been prepared. To the best
of our knowledge, this work is the first attempt to prepare the imi-
dazopyridine nucleus using a heterogeneous copper catalyst in a
one-pot multi-component process.
Fig. 1. Formation of propargylamine in the presence of [Cu(2-pymo)2] as catalyst
(Table 1, entry 1).
the rate of formation of the propargylamine depends on the con-
centration of the alkyne and of the iminium ion, being the forma-
tion of the iminium ion comparatively very fast.
After the reaction of propargylamine formation, the solid cata-
lyst was recovered by filtration and washed with dioxane and ace-
tone and dried at room temperature in a desiccator. No significant
losses of crystallinity and activity were observed after five runs
(see Figs. S1 and S2). No leached Cu was detected in the solution.
Nevertheless, the contribution of homogeneous catalysis by even-
tually leached species after hot filtration was studied and the
results in Fig. S3 show negligible activity in the filtrate. These ver-
ifications were made for all the reactions studied here, and in all
cases [Cu(2-pymo)2] was found to withstand the reaction condi-
tions without being altered in the least.
Since the reaction between the amine and the aldehyde pro-
duces a stoichiometric amount of water, we were prompted to
study the possible effect of water on the catalyst efficiency. To do
that, we repeated the reaction in the presence of either 1 or 5
equivalents of water intentionally added to the reaction medium.
Not only the presence of water has no negative effects on the reac-
tion, but it is even observed a clear shortening of the induction per-
iod upon addition of 5 equivalents of H2O.
2. Materials and methods
The Cu-MOFs were prepared according to the corresponding
procedures reported in the original references: [Cu(2-pymo)2] [8],
[Cu(im)2] [9], [Cu(BDC)] [15], and [Cu3(BTC)2] [16]. X-ray diffrac-
tion (Phillips X’Pert, Cu K
a radiation) was used to confirm the
expected crystalline structure of the materials. Benzaldehyde
(Aldrich, 99.5%) was freshly distilled prior to use, while all other
substances and reagents used were commercially available and
used as received. The reaction and analytic methodology are given
in Supplementary material.
All the catalytic reactions described in the text were carried out
in batch reactors. Aliquots were taken during the course of the
reaction and analyzed by GC using hexadecane as external stan-
dard. Specific conditions for each reaction (amounts of catalyst
and reagents, temperature, etc.) are indicated in the corresponding
Tables.
Blank experiments in the absence of catalyst produced only
very small amounts of propargylamine (Table 1, entry 2), and the
activity of [Cu(2-pymo)2] was comparable with that of homoge-
neous copper salts (entries 3–5). This indicates that incorporation
of the Cu2+ ions into framework positions to form the MOF does
not cause a significant decrease in the activity of copper to catalyze
this reaction. The activity of [Cu(2-pymo)2] is also comparable with
that of other heterogeneous copper-containing catalysts reported
in literature, such as copper-exchanged USY zeolite, that afforded
90% yield of propargylamine after 15 h under similar reaction con-
ditions (8 mol%Cu, 353 K, solvent free) [17].
To explore the scope of [Cu(2-pymo)2] as catalyst, different cat-
alyzed multi-component coupling reactions of aldehydes, amines,
and alkynes have been studied. Thus, when phenylacetylene was
replaced by an aromatic alkyne larger than phenylacetylene, the
reaction rate slightly decreased. Thus, the yield of propargylamine
obtained after 4 h of reaction in the case of phenylacetylene was
60%, while in the case of 1-ethynylnaphthalene was only 8% (entry
6), and a longer time is required to attain full conversion. These dif-
ferences in reactivity probably reflect the higher diffusion prob-
lems of the bulkier propargylamine to leave from the inner
surface of the MOF. This is not surprising if one considers that,
for the reaction to proceed it is necessary that the three molecules
3. Results and discussion
3.1. Formation of propargylamines by one-pot three-component
coupling reactions
Reaction between piperidine, paraformaldehyde, and phenyl-
acetylene at 313 K in the presence of [Cu(2-pymo)2] (1 mol%Cu)
gave 99% yield of the corresponding propargylamine (see Fig. 1
and Table 1, entry 1). The short induction period observed is not
related with the formation of the iminium ion (the primary prod-
uct of the reaction) since this step is very fast and not catalyzed
by the MOF. Its presence rather reflects the time needed for the
activation of phenylacetylene by the Cu-MOF. Indeed, we recently
reported the presence of a similar induction period in the 1,3-dipo-
lar cycloaddition of alkynes and azides catalyzed by Cu-MOFs [12].
However, when the catalysts were pre-treated with the alkyne for
a certain time period (up to 4 h) before adding the azide, the induc-
tion period gradually disappeared. A similar behavior was also
observed in the present case of propargylamine formation. Incuba-
tion of [Cu(2-pymo)2] with phenylacetylene for 2 h before adding
the amine and the aldehyde completely suppressed the induction
time. Note also in Fig. 1 that after the initial induction period,
the time-conversion plot roughly follows a second order law, since

I. Luz et al. / Journal of Catalysis 285 (2012) 285–291
287
Table 1
Scope of the one-pot three-component coupling reaction between amines, aldehydes and alkynes, to form the corresponding propargylamines.a
R3
R1
N
R1
N
O
cat
R4
H
R2
+
+
H
R2
H
R3
R4
Catalyst (mol%Cu)
R1R2NH
R3COH
R4C„CH
Temp (K)
313
%Yield time (h)
1
[Cu(2-pymo)2] (1%)
(HCOH)n
60 (4 h)
99 (21 h)
00
00
00
00
00
00
2
3
No catalyst
Cu(acac)2 (1%)
313
313
4 (22 h)
45 (6 h)
94 (21 h)
99 (6 h)
96 (6 h)
8 (4 h)
00
00
00
00
00
00
00
00
4
5
6
CuCl2 (1%)
CuI (1%)
[Cu(2-pymo)2] (1%)
313
313
313
99 (34 h)
00
00
00
7
8
[Cu(2-pymo)2] (1%)
[Cu(2-pymo)2] (1%)
313
313
31 (21 h)
76 (48 h)
55 (21 h)
99 (48 h)
00
00
00
9
[Cu(2-pymo)2] (1%)
313
<1 (21 h)
00
00
00
10
11
[Cu(2-pymo)2] (10%)
[Cu(2-pymo)2] (1%)
373
313
71 (21 h)
85 (48 h)
26 (4 h)
(HCOH)n
99 (21 h)
a
Reaction conditions: 1 mmol alkyne, 1.1 mmol aldehyde, 1.1 mmol amine, 1 mL dioxane, N2 atmosphere.
Scheme 1. Indole formation through a three-component coupling and 5-endo-dig cyclization tandem reaction.
meet in the right orientation within the pores of the MOF, this
becoming harder when the size of the components increases. The
results presented in Table 1 also show that [Cu(2-pymo)2] was also
able to catalyze the formation of propargylamine from terminal
alkylic alkynes, such as 1-octine (entry 7).
When formaldehyde was replaced by other alkylic aldehydes,
such as butyraldehyde (entry 8), the reaction also proceeded
smoothly. However, propargylamine is hardly formed when benz-
aldehyde was reacted (entry 9). We attributed this failure to the
difficulty to form the intermediate iminium species by addition
of piperidine to benzaldehyde, since this uncatalyzed reaction
should require higher temperatures. Indeed, when the reaction
temperature was increased from 313 to 373 K and the catalyst
loading to 10 mol%Cu (entry 10), full conversion could be achieved.
When piperidine was replaced by another secondary amine,
such as dipropylamine (entry 11), the expected product was also
formed quantitatively, although the initial reaction rate was lower
(compare entries 1 and 12). However, the reaction did not proceed
with primary amines, either alkylic or allylic such as n-propyl-
amine or aniline.
3.2. Preparation of indole and imidazopyridines: Tandem three-
component coupling and cyclization reactions
We have recently reported on the preparation of indole deriva-
tives catalyzed by supported gold nanoparticles and gold(III)-con-
taining MOFs [18,19]. The reaction involves the one-pot
three-component coupling of aldehydes, amines, and N-protected

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I. Luz et al. / Journal of Catalysis 285 (2012) 285–291
Table 2
nopyridine, benzaldehyde, and phenylacetylene was studied in
the presence of [Cu(2-pymo)2] (10 mol%Cu) at 393 K and toluene
as solvent. The amount of catalyst and the relatively elevated
temperature needed for this reaction reflect the difficulties for
the formation of the intermediate propargylamine from the
primary amine, as we already observed with aniline. The results
obtained are shown in Fig. 2 and Table 3. Under the reaction con-
ditions used, a maximum conversion of 61% was obtained after
30 h, with quantitative selectivity to the imidazopyridine (entry
1 in Table 3). Although this result is not too far from the values ob-
tained with homogeneous Cu2+ and Cu+ salts under similar condi-
tions (entries 8–11), we found that the [Cu(2-pymo)2] catalyst was
completely deactivated. Thus, when the catalyst recovered after
the reaction was used in a second catalytic cycle, almost no phen-
ylacetylene conversion was observed (less than 6% conversion after
30 h). This deactivation was not due to the instability of the MOF,
since its structure was fully preserved (as stated by XRD), but to
the irreversible adsorption of reaction products on the copper
MOF, since the products inside the pores could not be fully re-
moved by simple washing. Indeed, the XRD pattern of the solid fil-
tered after the reaction seems to indicate an important loss of
crystallinity of the material. However, upon thoroughly washing
the solid with CH2Cl2 to eliminate adsorbed products, an important
recovery of the peaks intensities is clearly observed (see Fig. S4).
In any case, under these reaction conditions the overall turn-
over number (TON) attained in the two catalytic cycles over
[Cu(2-pymo)2] was only 6.7 (mols product formed per mol of cop-
per used). This poor performance is not due to a lack of activity of
the copper centers but rather to poisoning of the catalyst by
irreversible pore blocking. We therefore looked for other copper-
containing metal–organic compounds, which would ideally con-
tain the same (or similar) active sites but at the same time should
also be less prone to poisoning. Among the different materials
tested (viz., [Cu3(BTC)2] and [Cu(im)2]; BTC = benzene tricarboxy-
late; im = imidazolate), the best results were obtained with the
copper terephthalate [Cu(BDC)] (BDC = benzene dicarboxylate)
[15]. This material contains the well known paddle-wheel copper
dimers, in which each dimmer coordinates to four terephthalate
molecules forming sheets which are then bonded through weak
stacking interactions. Each copper ion is further coordinated to a
DMF molecule in the apical position, which can be thermically re-
moved to expose then a vacant position. When [Cu(BDC)] was used
as catalyst for the formation of imidazopyridine under the same
reaction conditions, an almost complete conversion was attained
(97% imidazoypridine yield after 30 h), with full selectivity with re-
spect to the limiting reagent (phenylacetylene) [21]. Note that this
is a significant improvement with respect to [Cu(2-pymo)2] (com-
pare entries 1 and 4 in Table 3). [Cu(BDC)] shows almost the same
activity in a second catalytic run, although the activity sharply de-
creased in a third cycle (10% yield of the imidazopyridine after
30 h, see entries 5 and 6 in Table 3). The loss of activity of
[Cu(BDC)] is accompanied by changes in the crystalline structure
of the material upon repeated use (see Fig. S5), mainly consisting
in the appearance of new diffraction peaks at low angles (7.3°
and 8.0° 2h). It is well known that thermal activation of [Cu(BDC)]
produces changes in the X-ray diffraction pattern of the material,
which are completely analogous to what we observed upon cata-
lytic use [15]. As reported by Carson et al. [15], thermal desorption
Formation of indole derivatives through domino three-component coupling and 5-
endo-dig cyclization.a.
Entry
Catalyst
Yield (%)b
t (h)
TOF (hꢀ1
)
1
2
3
4
5
6
[Cu(2-pymo)2]
>95
60
36
38
93
18
6
14
14
14
2
7
3
12
40
52
70
c
AuCl3
c
Au/ZrO2
Au(III) Schiff base complexc
IRMOF-3-SI-Auc
CuCl2
>95
a
Reaction conditions: Ethynylaniline (0.1 mmol), piperidine (0.12 mmol), para-
formaldehyde (0.2 mmol), catalyst (1 mol% metal), 1,4-dioxane (1 mL) as solvent at
313 K.
b
Isolated yield based on ethynylaniline. Selectivity to the indole was >99% in all
cases.
c
Data taken from Ref. [19].
ethynylaniline followed by 5-endo-dig cyclization, according to
Scheme 1.
The above reaction is an example of the versatility of propargyl-
amines as chemical intermediates for the preparation of natural
products and drugs, since they can be used, for instance, as starting
materials for preparing important molecules such as indole
derivatives. Since the formation of the indole passes through an
intermediate propargylamine, and given the good performance of
[Cu(2-pymo)2] for propargylamine synthesis, we have studied the
application of this and other copper-containing MOFs as catalysts
for the preparation of indoles. The results obtained are summa-
rized in Table 2, in which a comparison is also made with a homo-
geneous copper salt and various gold catalysts.
As it can be seen in Table 2, [Cu(2-pymo)2] was found to be an
active and selective catalyst for this tandem reaction to the indole
formation: The intermediate propargylamine was not detected at
the end of the reaction, and the sole product formed was the in-
dole. The activity of this Cu-MOF catalyst, expressed as turnover
frequency (mols of indole formed per mol of copper used per unit
of time), was TOF = 7 hꢀ1 (entry 1 in Table 2), which is comparable
with that obtained for gold salts (AuCl3, see entry 2) or supported
gold nanoparticles (Au/ZrO2, entry 3). However, the activity of
[Cu(2-pymo)2] is low compared with CuCl2 (entry 6) or with that
recently reported for Au(III) Schiff base complexes, either as homo-
geneous complexes (entry 4) or as heterogeneized catalysts
prepared by post-synthesis modification of an existing MOF (entry
5) [19]. Nevertheless, the crystalline structure of the MOF was not
affected by the reaction conditions, and the material can be reused
for at least five consecutive catalytic cycles without significant loss
of activity.
As mentioned above, propargylamines can also be used as inter-
mediates for the preparation of other heterocycles. An interesting
example is the preparation of imidazopyridine derivatives, given
the presence of this nucleus in a family of anxiolytic drugs, such
as alpidem or zolpidem. Imidazopyridines can be prepared from
2-aminopyiridine, an aldehyde, and a terminal alkyne through a
tandem one-pot three-component coupling reaction, leading to
the formation of an intermediate propargylamine, and ensuing
5-exo-dig cyclization [20], according to Scheme 2.
To investigate the potential of the copper MOF for the prepara-
tion of imidazopyridine derivatives, the reaction between 2-ami-
Scheme 2. Formation of imidazopyridine compounds through a three-component coupling and 5-exo-dig cyclization tandem reaction.

I. Luz et al. / Journal of Catalysis 285 (2012) 285–291
289
Fig. 2. Imidazopyridine yield obtained in the presence of different copper salts and Cu-MOF catalysts. The metal loading (mol%) is indicated in parentheses.
effect: On one hand, it effectively yields the lamellar compound
according to the XRD pattern (see Fig. S5); i.e., the reverse process
in Scheme 3. On the other hand, DMF washes away any possible
reaction product that can be adsorbed on the catalyst surface, as
evidenced by the brownish color of DMF at the end of the treat-
ment. Therefore, we found that heating in DMF is an adequate
treatment to regenerate the Cu-MOF catalyst. Indeed, regenerated
[Cu(BDC)] shows practically the same activity for the production of
imidazopyridine that the freshly prepared compound (see Table 3
and Fig. 2).
We carried out an additional set of experiments that revealed a
further advantage of using Cu-containing MOFs instead of copper
salts as catalysts for the three-component coupling reaction. Note
that formation of imidazopyridine following the proposed
synthetic procedure implies the use of a terminal alkyne as one
of the three components (in our case, phenylacetylene). It is well
known that terminal alkynes in the presence of copper salt cata-
lysts and in the presence of air can produce the Glaser’s oxidative
coupling products, according to Scheme 4. This side reaction could
compete with the three-component coupling, resulting in a de-
crease of the overall imidazopyridine yield. Therefore, when cop-
per salts are used as catalysts for imidazopyridine formation, it is
necessary to work under an inert atmosphere and to use degassed
solvents to avoid the formation of Glaser’s coupling products, as
was done in the experiments reported in Table 3 [20]. In order to
evaluate the relevance of the competing Glaser reaction, the prod-
uct distributions were compared when the reaction was performed
in either N2 or air, and using [Cu(BDC)] and various copper salts as
catalysts. The results obtained are reported in Table 4.
As it can be seen there, when CuCl2 is used as catalyst the for-
mation of the Glaser product is largely prevented when a N2 atmo-
sphere is used (see entry 3). However, the amount of undesired
product formed increases considerably when N2 was replaced with
air (entry 4), clearly becoming the main reaction product under
oxidative conditions. Note that the phenylacetylene conversion
after 30 h was also higher when the reaction was performed in
the presence of air. The relevance of the Glaser reaction was even
larger when copper acetate was used as catalyst. In this case, even
with the use of an inert atmosphere, it was very difficult to avoid
formation of the byproduct, since traces of O2 seems to be enough
to re-oxidize the Cu+ ions formed and to regenerate the catalytic
species. Surprisingly, when [Cu(BDC)] was used as catalyst, we
hardly observed any difference concerning both phenylacetylene
conversion and selectivity to the imidazopyridine, since we did
Table 3
Formation of imidazopyridine through domino three-component coupling and 5-exo-
dig cyclization.a.
Entry
Catalyst (mol%Cu)
t (h)
Yield (%)
1
2
3
4
5
6
7
8
9
[Cu(2-pymo)2] (10)
[Cu(2-pymo)2] (10) (2nd use)
No catalyst
30
30
30
30
30
30
30
16
16
16
16
61b
6b
<1b
97b
95b
10b
93b
10c
55c
74c
93c
[Cu(BDC)] (10)
[Cu(BDC)] (10) (2nd use)
[Cu(BDC)] (10) (3rd use)
[Cu(BDC)] (10) (regenerated)
Cu(OTf)2 (5)
CuCl (10)
CuCl (50)
10
11
CuCl (5)+ Cu(OTf)2 (5)
a
Reaction conditions: Phenylacetylene (1 mmol), 2-aminopyridine (1.1 mmol),
benzaldehyde (1.2 mmol), toluene (1 mL) at 393 K under inert (N2) atmosphere.
b
Determined by GC using hexadecane as external standard.
Data taken from Ref. [20].
c
of the DMF molecules coordinated to the copper sites results in the
formation of a new crystalline structure in which the original
Cu(BDC) sheets are connected one to another by formation of
new bonds between Cu and O belonging to two adjacent layers,
according to Scheme 3. Note that, while the lamellar structure con-
tains accessible Cu sites, the structural transformation leaves the
copper sites completely blocked by the ligands and inaccessible
to the substrates. This explains the low catalytic activity of the
new compact structure. The material recovered after two cycles
still contains a significant fraction of the lamellar material, while
after three cycles the solid consists mainly in the compact struc-
ture (see Fig. S5).
According to Carson et al. [15], the structural transformation of
[Cu(BDC)] from a lamellar to a compact structure upon DMF
desorption can be reversed by re-adsorption of molecules contain-
ing carbonyl groups, as the authors demonstrated by treating the
desolvated solid with N-methylpyrrolidone. Analogously, when
pure desolvated [Cu(BDC)] was treated with DMF at 405 K for
2 h, we observed that the material showed a diffraction pattern
characteristic of the lamellar compound. Thus, we submitted the
spent catalyst recovered after three catalytic runs (mainly consist-
ing in the compact structure) to a similar treatment with DMF,
with the aim of recovering the pristine lamellar structure (which
is the catalytically active phase). This treatment has a twofold

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I. Luz et al. / Journal of Catalysis 285 (2012) 285–291
N
O
O
O
O
Cu
O
O
O
O
Cu
O
O
O
O
O
Cu
O
O
O
N
Cu
O
O
N
O
O
O
O
O
Cu
O
O
O
Cu
O
-DMF
O
O
O
O
Cu
O
O
+DMF
Cu
O
O
O
O
N
O
O
Cu
O
N
O
O
O
O
Cu
O
O
O
Cu
O
O
O
O
Cu
O
O
O
N
Scheme 3. Reversible crystalline phase transformation of [Cu(BDC)] from the lamellar to the compact structure upon desorption/adsorption of DMF.
observe formation of the Glaser product as well. In conclusion,
when [Cu(BDC)] is used as catalyst for the formation of the imi-
dazopyridine, the avoidance of O2 in the reaction medium becomes
unnecessary, which largely simplifies the reaction setup.
4. Conclusions
Scheme 4. Glaser oxidative coupling of phenylacetylene.
We have seen that different Cu-MOFs are solid catalysts able to
catalyze a three-component coupling reaction to obtain propargyl-
amines with an excellent selectivity and a reasonable scope. Their
activity is similar to the reported with other solid catalysts and
homogeneous Cu catalysts. Thus, Cu-MOFs have shown to be par-
ticularly efficient catalysts for reactions implying the formation of
copper-acetylide intermediates.
Table 4
Influence of the atmosphere on the formation of imidazopyridine and Glaser oxidative
coupling product.a
Entry Catalyst
Atmosphere Conv.
(mol%)b
%Yield
IPc
%Yield
Glaserc
1
2
3
4
5
6
[Cu(BDC)]
CuCl2
N2
Air
N2
Air
96
96
97
56
16
40
30
n.d.
n.d.
2
34
15
32
Owing to the good results obtained for the three-component
coupling reaction, two tandem reaction were also attempted that
include and additional step to produce indoles and imidazopyri-
dines. [Cu(2-pymo)2] was active and selective, though it deacti-
vates irreversibly during the synthesis of imidazopyridines, due
to pore blocking by the product occluded in the micropores. This
problem has been overcome by using [Cu(BDC)]. The material
undergoes a progressive structural phase change during the course
of the reaction, passing from a catalytically active lamellar struc-
ture to a catalytically inactive compact structure, accompanied
by the loss of activity after two catalytic cycles. However, this
structural phase change can be reversed by treating the solid with
DMF under reflux, which recovers the lamellar structure and con-
sequently the catalytic activity of the fresh catalyst. Finally,
[Cu(BDC)] was found to be inactive for the Glaser homocoupling
reaction of phenylacetylene, which is a side reaction that can
otherwise compete with the imidazopyridine formation when cop-
per salts are used as catalysts under oxidizing conditions. This
inactivity of [Cu(BDC)] for the Glaser reaction makes unnecessary
the use of an inert atmosphere for the three-component coupling
reaction, which simplifies the reaction setup as compared to cop-
per salt catalysts.
97
60
84
70
94
Cu(CH3COO)2 N2
Air
a
Reaction conditions: Phenylacetylene (1 mmol), 2-aminopyridine (1.1 mmol),
benzaldehyde (1.2 mmol), toluene (1 mL), Cu-catalyst (10 mol%Cu) at 393 K under
either air or N2 atmosphere.
b
Conversion after 30 h as determined by GC using hexadecane as external
standard and referred to the limiting reagent, phenylacetylene.
c
Yield to the imidazopyridine (IP) or to Glaser coupling product (Glaser). Note
that formation of the Glaser coupling product requires two equivalents of phenyl-
acetylene, while imidazopyridine consumes only one.
not detect formation of the Glaser product even at the trace level.
This result probably indicates that the coordination of the copper
centers in the MOF strongly stabilizes the +2 oxidation state of
the metal, thus resulting in a completely inactive catalyst for the
Glaser reaction. Note in this sense that even when [Cu(BDC)] was
contacted with pure phenylacetylene under air and at 393 K (i.e.,
same reaction conditions but without the other two components
necessary for the formation of imidazopyridine), we did not

I. Luz et al. / Journal of Catalysis 285 (2012) 285–291
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Financial support by Ministerio de Educación y Ciencia e Inno-
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ER.INGENIO 2009), Generalidad Valenciana (GV PROMETEO/2008/
130) and the CSIC (Proyectos Intramurales Especiales 20108
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are gratefully acknowledged for a research contract to I.L.
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Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jcat.2011.10.001.
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