MIL-101 supported highly active single-site metal catalysts for tricomponent coupling

Article abstract of DOI:10.1016/j.apcata.2018.10.020

Metal-organic frameworks with regular pore structures provide powerful platforms for the design of single-site metal catalysts for chemical transformation. In this paper, we develop a facile, stable and recyclable MOF-supported Cu(II) catalyst, MIL-101-SO₃Cu. It shows extremely high activity for the A³ coupling of alkynes, aldehydes and amines. The turnover frequency can reach 6.8 × 10⁵ h^?1 under neat conditions, which is the highest so far reported for the reaction. The high activity is because the specific structure of the MIL-101-SO₃ support enables a single-site dispersion and an unhindered open environment for the metal ion. MIL-101-SO₃Cu also exhibits high activity for the one-pot cascade reactions combining A³ coupling and 5-endo-dig cyclization.

Full text of DOI:10.1016/j.apcata.2018.10.020

Accepted Manuscript
Title: MIL-101 supported highly active single-site metal
catalysts for tricomponent coupling
Authors: Weng-Jie Sun, En-Qing Gao
PII:
S0926-860X(18)30518-0
DOI:
Reference:
https://doi.org/10.1016/j.apcata.2018.10.020
APCATA 16849
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
5-9-2018
17-10-2018
19-10-2018
Please cite this article as: Sun W-Jie, Gao E-Qing, MIL-101 supported highly active
single-site metal catalysts for tricomponent coupling, Applied Catalysis A, General
(2018), https://doi.org/10.1016/j.apcata.2018.10.020
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Cover Page
MIL-101 supported highly active single-site metal catalysts for
tricomponent coupling
Weng-Jie Sun and En-Qing Gao*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry
and Molecular Engineering, East China Normal University, Shanghai 200062, China
Corresponding author:
En-Qing Gao
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry
and Molecular Engineering, East China Normal University, Shanghai 200062, China
Fax: +86-21-62233404
E-mail: eqgao@chem.ecnu.edu.cn
Graphical abstract
1

Highlights
 A highly active Cu(II)-functionalized MOF catalyzes the A3 (alkyne-aldehyde-amine)
coupling reaction.
 The heterogeneous catalyst exhibits a record high TOF of 6.8×105 h-1 and is recyclable.
 The catalyst also exhibit high activity for the construction of indole rings through cascade
A3 coupling and intramolecular cyclization reactions.
 The high activity arises from the single-site dispersion and the unhindered open
environment of the metal ion.
Abstract:
Metal-organic frameworks with regular pore structures provide powerful platforms for the
design of single-site metal catalysts for chemical transformation. In this paper, we develop a
facile, stable and recyclable MOF-supported Cu(II) catalyst, MIL-101-SO3Cu. It shows
extremely high activity for the A3 coupling of alkynes, aldehydes and amines. The turnover
frequency can reach 6.8105 h-1 under neat conditions, which is the highest so far reported for
the reaction. The high activity is because the specific structure of the MIL-101-SO3 support
enables a single-site dispersion and an unhindered open environment for the metal ion.
MIL-101-SO3Cu also exhibits high activity for the one-pot cascade reactions combining A3
coupling and 5-endo-dig cyclization.
Keywords: metal-organic frameworks; single-site catalysis; copper(II) catalysis;
heterogeneous catalysis; A3 coupling
2

1. Introduction
The multicomponent reaction of an alkyne, an aldehyde and an amine, known as A3 coupling,
has attracted much interest because it provides an efficient, convenient and atom-economic
access to propargylamines, which are crucial components of many natural products and
versatile intermediates for biologically active and pharmacological compounds [1-4]. The
reaction is catalyzed by various metal compounds, including those with Au [5, 6], Ag [7, 8],
and Cu [9-11], which are generally good at alkyne C-H activation. Because heterogeneous
catalysis can have the advantages such as simple separation, easy recyclability of catalysts
and good adaptability to continuous-flow processes, particular efforts have been devoted to
the development of supported A3 catalysts on inorganic (oxides, zeolites, silicas, graphenes),
organic, or hybrid solids [8, 12-17]. However, the catalysts are still far from satisfactory. A
major challenge is to enhance the catalytic activity so as to reduce the catalyst dosage and the
reaction time/temperature. From this viewpoint, isolated single-site metal catalysts are highly
intriguing. In addition, it is desirable to avoid tedious synthetic steps, eco-unfriendly
solvents/additives and air sensitivity during the preparation and the use of the catalysts.
Metal-organic frameworks (MOFs), which feature diverse and tailorable crystalline
structures, porosity and functionalities, have emerged as versatile platforms to engineer solid
catalysts [18, 19]. MOFs can behave as catalysts themselves with the organic or inorganic
components containing the active sites. More remarkably, MOFs have great potential as
catalyst supports, with the desired active sites being installed onto the organic/inorganic units
or encapsulated within the pore space by diverse postsynthetic approaches. In particular, the
regular pore structure can afford isolated single catalytic sites in favor of high catalytic
activity [20-23].
MOF-based catalysts for A3 coupling have been reported recently, including a few
Cu-MOFs utilizing the intrinsic metal sites and a few Zn-MOF supported Cu(I), Ag(0),
Au(0/III) and Pd(0) catalysts [2, 7, 24-26]. The study still remains in its infancy. We are
focused on MIL-101-SO3 supported metal catalysts for the following reasons. The facile
preparation, the high porosity and the excellent stability of the MIL-101-type MOF are
advantageous to postsynthesis and catalysis [27]; the anionic sulfonate groups provide facile
3

handles to immobilize open metal cations through charge-assisted coordination [28-30]; the
MOFs with varying metal ions provides nice systems for studying the metal dependence of
catalytic performance. We recently reported that MIL-101-SO3Ag is a recyclable and very
active catalyst for A3 coupling, the turnover frequency (TOF) reaching up to 6.6103 h-1 [30].
Considering the requirement of sustainable chemistry for earth-abundant metal catalysts, we
initialized and present here a study on MIL-101-SO3Cu. To our satisfaction, the Cu(II)
catalyst shows even higher activity, with a record high TOF of 6.8105 h-1 for A3 coupling.
We attribute the high activity to single-site dispersion and unhindered open environments
enabled by the MIL-101-SO3 support. We also extend the study to tandem A3 coupling and
cyclization reactions.
2. Experimental
2.1 Synthesis of MIL-101-SO3Cu
MIL-101-SO3H was prepared according to a procedure described elsewhere [30]. Different
Cu(II) salts and solvents were tried for the synthesis of MIL-101-SO3Cu (Table S1). For
typical preparation, a given amount of Cu(II) salt was dissolved in a solvent, and
MIL-101-SO3H (200 mg, 0.209 mol) was added. The mixture was stirred under room
temperature for 12 h. The solid was collected by filtration, washed with water for five times
and with CH3CN twice, and dried at 110 C for 4 h.
2.2 Typical procedure for A3 coupling reactions
A mixture of phenylacetylene (0.55 ml, 5.0 mmol) and piperidine (0.50 ml, 5.0 mmol) was
added under stirring to a 25 ml flask containing dried MIL-101-SO3Cu (6.0 mg, containing
2.6 μmol Cu) and paraformaldehyde (195 mg, 6.5 mmol). After stirred at 80 C for a given
time, the slurry was centrifuged, and the supernatant was diluted with CDCl3 and subjected to
1H NMR analysis. The recycling tests were performed on a larger scale under the typical
conditions, with the starting amount of all reagents increased to 10 times the aforementioned
amount. After each run, the solid obtained by centrifugation was washed with
dichloromethane (20 ml  3) and dried overnight for the next run.
2.3 Typical procedure for the cascade reactions
4

Paraformaldehyde (40 mg, 1.3 mmol), piperidine (100 μl, 1.0 mmol) and ethyl acetate (1 ml)
was added under stirring to a 25 ml flask containing dried MIL-101-SO3Cu (24 mg,
containing 10 μmol Cu). After the temperature was raised to 60 C, N-tosyl-2-ethynylaniline
(270 mg, 1.0 mmol) was added and the mixture was stirred for 0.5 h. The slurry was
centrifuged, and the yield was obtained from 1H NMR of the supernatant dissolved in CDCl3.
2.4 Characterization
X-ray powder diffraction patterns of the samples were measured using a Rigaku Ultima IV
X-ray Diffractometer with Cu Kα radiation (λ = 1.5418 Å) at a scanning rate of 10 /min, with
accelerating voltage and current of 35 kV and 25 mA, respectively. Nitrogen adsorption and
desorption isotherm measurements were performed on a Micromeritics ASAP2020 analyzer
at 77K. Scan electron microscopy (SEM) and elemental distribution map study was carried
out with a S-4800 HITACHI scanning electron microscope. Transmission electron
microscopy (TEM) images were recorded with a JEOL JEM-2100 microscope. FT-IR spectra
were recorded in the range 500 − 4000 cm−1 using KBr pellets on a Nicolet NEXUS 670
spectrophotometer. The metal amount was detected by inductively coupled plasma atomic
emission spectroscopy (ICP-AES) using an IRIS Intrepid II XSP spectrometer. Proton nuclear
magnetic resonance spectra (1H NMR) were obtained on a Bruker Ascend 400 (400 MHz)
spectrometer. The hydrogen temperature-programmed reduction (H2-TPR) and
temperature-programmed desorption of ammonia (NH3-TPD) were performed on a
Micromeritics autochem 2920 instrument. For the purpose, 0.050 g sample was put into a
U-shaped quartz tube and treated in argon (20 mL/min) at 150 C for 30 min. The TPR and
TPD curves were obtained at the 10 C / min rate.
3. Results and discussion
3.1 Catalyst preparation and characterization
MIL-101-SO3Cu was synthesized by a facile two-step protocol (Scheme 1): hydrothermal
synthesis of MIL-101-SO3H from 2-sulfoterephthalic acid and CrO3 [30, 31], followed by
simple room-temperature cation exchange in an aqueous solution containing excessive
5

Cu(ClO4)2 (3.5 equivalents relative to the sulfonate group). The solid was filtered and
thoroughly washed with water until no Cu(II) was detected by DDTC (sodium
diethyldithiocarbamate).
Scheme 1. Synthesis of the single-site catalyst MIL-101-SO3Cu
Powder X-ray diffraction (PXRD, Fig. 1a) confirms that the framework remains intact after
Cu(II) complexation. According to ICP-AES analysis, the loading amount of Cu(II) is about
14 mol% with respect to the sulfonic groups in the MOF. The loading amount was only
slightly increased to 18 mol% when the quantity of Cu(ClO4)2 used in the preparation was
increased by 10 times. Subsequent characterization and catalytic study were performed using
the material with 14 mol% Cu(II) loading. To see if the anion of the Cu(II) source has
influence on Cu(II) loading, different Cu(II) salts (CuCl2, Cu(BF4)2 and Cu(ClO4)2) have been
used to react with MIL-101-SO3H. ICP-AES analysis suggested that the loading amount of
Cu(II) is always around 14 mol%, with no appreciable dependence on the anion in the Cu(II)
source. The FTIR spectra of the products are essentially identical (Fig. 1b), with no
-
-
indications of absorption bands characteristic of BF4 or ClO4 . The results show that Cu(II) is
not charge compensated (and coordinated) by the exogenous anions but by sulfonate from the
framework. The IR absorptions at 1230, 1180, and 1080 cm-1 arising from the O=S=O and
S-O stretching vibrations show no significant change after H+-Cu2+ cation exchange.
6

Fig. 1. PXRD profiles (a) and FTIR spectra (b) of MIL-101-SO3H and MIL-101-SO3Cu from different
Cu(II) sources
SEM and TEM images were taken for MIL-101-SO3H and MIL-101-SO3Cu (Figs. S1 and
S2). The materials show no significant change in morphology before and after metalation, and
no metal nanoparticles were found in the TEM images of MIL-101-SO3Cu. Element mapping
(Fig. S3) suggest that Cr and Cu are uniformly distributed in MIL-101-SO3Cu, and the Cu:Cr
atomic ratio (0.11) according to energy dispersive spectroscopy (EDS) is in good agreement
with the ICP analysis. X-ray photoelectron spectroscopy (XPS) with MIL-101-SO3Cu (Fig. 2a)
revealed Cu 2p3/2 and 2p1/2 peaks at 934.5 and 954.7 eV, respectively, together with the
shake-up satellite signals, confirming the Cu(II) state [32]. The H2-TPR profile of
MIL-101-SO3H begins to rise slightly above 350C and shows a strong peak at 505 C (Fig.
S4). This should be due to decomposition of the organic component of the MOF in the
reductive atmosphere rather than reduction of the Cr(III) center. The H2-TPR profile of
MIL-101-SO3Cu shows a weak shoulder peak at 330 C and a strong peak at 485 C. Because
the shoulder peak is absent before metallation, it can be safely attributed to the reduction of
7

Cu(II). Meanwhile, the main peak is shifted by about 20 C to lower temperature, which could
indicate that the framework decomposition is promoted by copper. The NH3-TPD profiles are
shown in Figure S5. For MIL-101-SO3H, the broad desorption peak around 80-200 C can be
due to the open Cr(III) sites of the framework [33], and the peak at about 340 C can be
assigned to the strong acidic sulfonic sites [34]. For MIL-101-SO3Cu, the two
framework-originated peaks remain with some shifts toward lower temperatures. An
additional broad signal was observed around 230 C, which we tentatively ascribe to the Cu(II)
sites.
Fig. 2. (a) Cu 2p XPS spectra of MIL-101-SO3Cu before and after catalytic use (The peaks marked with *
are the shake-up satellites) (b) Nitrogen adsorption (solid) and desorption (open) isotherms of
MIL-101-SO3H and MIL-101-SO3Cu
According to nitrogen adsorption isotherm at 77 K (Fig. 2b), the Brunauer−Emmett−Teller
(BET) specific surface area of MIL-101-SO3Cu is 1590 m2/g, which is somewhat lower than
that of MIL-101-SO3H (1761 m2/g) and higher than that of MIL-101-SO3Ag (1497 m2/g, with
21 mol% Ag(I) loading) [30]. The results indicate that the MOF remains highly porous after
Cu modification.
8

3.2 Catalytic A3 coupling over MIL-101-SO3Cu
To evaluate the catalytic performance, the A3 coupling reaction of phenylacetylene,
paraformaldehyde and piperidine was performed over MIL-101-SO3Cu (14 mol% Cu loading)
at a low dosage of 0.05 mol% (the amount of Cu(II) relative to phenylacetylene) without any
protecting atmosphere. Solvent survey at 80 C (entries 1-3, Table 1) suggested that DMF and
toluene are better than 1,4-dioxane and afford moderate yields in 15 min. To our satisfaction,
the solvent-free reaction (entry 4) gave the best results, the yield reaching 99% (isolated yield,
98%) in 15 min, with a TOF up to 7.9×103 h-1 (1.0×104 h-1 in 5 min). Hence the neat condition
was chosen for further investigation. The reaction rate is strongly dependent on temperature.
At room temperature (25C), no propargylamine product was detected even after much
prolonged time. The reaction at 40 C yielded the product nearly quantitatively in 6 h, and
further increasing the reaction temperature led to remarkable increase in reaction rate (entries
4-8). At 100 C, the reaction gave a yield of 94% in only 5 min (entry 5), the TOF being as
high as 2.2×104 h-1.
Table 1. Catalytic data for A3 coupling of phenylacetylene, paraformaldehyde and piperidinea
Entry
Catalyst
Time (min)
Yield (%)b
TOF (h-1)
T (C)
80
1c
2d
3e
4
MIL-101-SO3Cu
MIL-101-SO3Cu
MIL-101-SO3Cu
MIL-101-SO3Cu
MIL-101-SO3Cu
MIL-101-SO3Cu
MIL-101-SO3Cu
MIL-101-SO3Cu
MIL-101-SO3Cu
-
15
15
18
72
59
1.4×103
5.8×103
4.7×103
80
80
15
80
5/15
5
43/99 (98f) 1.0×104/7.9×103
5
100
60
94
84
2.2×104
1.7×103
6
60
7
40
60/360
24h
5
19/99
trace
57
380/330
8
25
-
9g
10
11
100
100
100
6.8×105
120
120
12
-
-
MIL-101-SO3H
10
a
Reaction conditions: phenylacetylene, 5.0 mmol; paraformaldehyde, 6.5 mmol; piperidine, 5.0 mmol,
catalysis, 0.05 mol% (or specified otherwise); solvent-free or specified otherwise. b Calculated via 1H NMR.
c
d
e
Solvent: 2 ml 1,4-dioxane. Solvent: 2 ml toluene. Solvent: 2 ml DMF. f Isolated yield. g Catalyst
amount: 0.001 mol%.
9

Encouraged by the high catalytic activity, the dosage of MIL-101-SO3Cu was further
decreased (entry 9). With an extremely low dosage of 0.001 mol%, the reaction at 100 C can
give a moderate yield of 57% within 5 min, the TOF being as high as 6.8105 h-1. To
determine the active site, control experiments were performed without any catalyst or with the
MIL-101-SO3H precursor as potential catalyst. Both reactions gave very low yields (~10%,
entries 10 and 11) even in much prolonged time. The results clearly confirm that the Cu(II)
site is responsible for the high catalytic activity of MIL-101-SO3Cu.
To our delight, MIL-101-SO3Cu has the highest activity ever reported for the A3 coupling
of phenylacetylene, paraformaldehyde and piperidine. The optimized catalytic data of
previous heterogeneous catalysts for the reaction are collected in Table 2. Diverse conditions
have been used for different catalysts. Because the catalytic activity generally increases with
temperature, the data for MIL-101-SO3Cu at different temperatures are included in the table
for reasonable comparison. As can be seen, a variety of catalysts, including a few MOF-based
ones, have been used at 40 - 120 C with dosages of 0.3-10 mol%, the TOFs ranging from 0.3
to 103 h-1 at the yield levels of 80-99% in 0.5-24 h (entries 1-10). By contrast, a much lower
dosage of MIL-101-SO3Cu can catalyze the reaction with much higher efficiency. With the
0.05 mol% dosage and at the yield levels of 94-99%, the TOFs over MIL-101-SO3Cu vary
from 330 h-1 at 40 C to 22000 h-1 at 100 C (entries 11-13). A still lower dosage of 0.001 mol%
afforded the extremely high TOF of 680000 h-1 (entry 14). The TOF value is four times higher
than the previous record high value (~150000 h-1), which was reported recently for
Ag@IRMOF-3 (Ag nanoparticles encapsulated within IRMOF-3) at 120 C under
microwave-assisted heating conditions (entry 15) [7]. It should be noted that microwave
irradiation makes vital contribution to the high activity of Ag@IRMOF-3. When used at 120
C without microwave, Ag@IRMOF-3 showed a TOF of 1400 h-1 (entry 16) [7], which is
much lower than the values for MIL-101-SO3Cu at 100 and even 80 C.
10

Table 2. Comparison of different A3-reaction catalyst
Entry
1
Catalyst
Cu(2-pymo)2
Ag-NHC
Dose (mol%)
t (h) Yield (%) TOF (h-1)
Ref.
[35]
T (C)
40
1
2
21
6
99
91
89
90
99
95
93
80
93
99
99
94
57
80
44
33
40
4.7
7.6
2
40
[36]
3
Hg2Cl2
5
70
4
4.4
[37]
4
GO-Fe3O4
0.3
4.4
5
90
16
18.8
0.94
38.0
25.8
0.40
103
330
[38]
5
Au@SH-CNC
Ag@SBA-15
Cu@PS-ala
80
24
[39]
6
100
100
120
120
40
0.5
6
[40]
7
0.6
10
[41]
8
InCl3
20
[42]
9
Au@MOF-199
MIL-101-SO3Cu
MIL-101-SO3Cu
MIL-101-SO3Cu
MIL-101-SO3Cu
Ag@IRMOF-3
Ag@IRMOF-3
MIL-101-SO3Ag
MIL-101-SO3Ag
1.8
0.05
0.05
0.05
0.001
0.09
0.09
0.06
0.05
0.5
6
[5]
10
11
12
13
14
15
16
17
This work
80
0.25
0.083
0.083
7.9×103 This work
2.2×104 This work
6.8×105 This work
100
100
120 (MW)b 0.017
1.5×105, a
1.4×103, a
6.6×103
3.2×103
[7]
[7]
120
100
80
1
0.083
0.25
[30]
[30]
a Calculated based on the exposed Ag surface atoms. b MW = microwave
The superior catalytic activity of MIL-101-SO3Cu could be because the MIL-101-SO3
support enables full exposure and complete site-isolation of the metal ions. Generally, the key
to A3 catalysis is the terminal C-H activation of alkyne, which involves an intermediate 
complex with η2 side-on coordination of CC to a metal site [2]. For a metal ion chelated by
multidentate ligands or a nodal metal site in MOFs, there could be steric hindrance for the
side-on coordination, even if the metal site is coordinatively unsaturated. For metal
nanoparticles, the utilization of metal atoms is limited because they are not single-site isolated.
11

By contrast, the SO3M groups in MIL-101-SO3M are well isolated from each other and stick
out from organic linkers towards the pore space, so each metal ion has a very open
environment (probably with easily leaving water ligands) and can be efficiently accessed by
substrates without significant steric hindrance. The advantages of MIL-101-SO3 as metal-ion
support are also illustrated by MIL-101-SO3Ag. Although not conscious of the advantages in
our previous report [30], we showed that MIL-101-SO3Ag shows a high TOF of 6600 h-1 at
100 C for the A3 coupling reaction (entry 16, Table 2). A new control experiment with
MIL-101-SO3Ag revealed a TOF of 3200 h-1 at 80 C (entry 17, Table 2). The TOFs over
MIL-101-SO3Ag are lower than that of MIL-101-SO3Cu but significantly higher than those
over other catalysts, including Ag@IRMOF-3 under microwave-free conditions. The different
activities of MIL-101-SO3Cu and MIL-101-SO3Ag can be due to the different nature of the
metal centers.
Fig. 3. Recycle tests of MIL-101-SO3Cu
It is highly desirable that a heterogeneous catalyst can be easily recycled. Recycle tests
with MIL-101-SO3Cu showed that it can be used for at least five consecutive runs after
simple centrifugal separation and washing, without significant deterioration in activity (Fig.
3). The slight decrease in yield could be due to the mass loss of the catalyst during work-up
and separation. ICP-AES analysis with the used catalyst indicated no appreciable leaching of
Cu(II) (within the experimental error) during the catalytic reaction. This should be because
12

the Cu(II) ion is charge compensated by the framework and the reaction system does not
contain anionic coordinative species that compete with sulfonate for Cu(II) ions.
The similarity of the PXRD profiles after used for 1-4 turns suggests that the MIL-101
framework is essentially retained after the catalytic reactions (Fig. 4). The IR spectrum also
shows no significant changes except that the used catalyst displays weak IR absorptions at
2862, 2949 and 3210 cm−1 (Fig. 5). These bands also appear if the fresh catalyst is treated
with only piperidine, so they are attributable to ν(C-H) and ν(N-H) of the piperidine
molecules adsorbed in the MOF. The piperidine molecules cannot be completely removed by
washing, which could be due to the coordination interactions of piperidine with Cu(II) or the
acid-base reaction of piperidine with the extra SO3H group in the MOF. The recycle tests
indicate that the adsorbed piperidine has no significant impact on the catalytic performance.
XPS revealed the Cu 2p3/2 and 2p1/2 peaks shift slightly to lower energies after catalytic use,
which could be ascribed to coordination of piperidine. The retention of the shake-up satellites
indicates that Cu remains in the paramagnetic +II state [32], and there are no indications for
reduction of Cu(II) to Cu(I) or Cu(0). Furthermore, no Cu(0) particles were found in the TEM
images of MIL-101-SO3Cu after the catalytic reaction (Fig. S2 (b)).
Fig. 4. PXRD profiles of MIL-101-SO3Cu for recycling runs of the catalytic reaction
13

Fig. 5. FTIR spectra of MIL-101-SO3Cu before and after catalytic use and after treatment with piperidine
The application scope of the catalyst was examined for different substrates. As shown in
Scheme 2, aromatic terminal alkynes with either electron-donating or electron-withdrawing
substituents react rapidly with paraformaldehyde and piperidine to reach complete conversion
within 15 min (1-4). 4-Ethynylpyridine, a heterocyclic alkyne, could also achieve 95%
conversion in 30 min (5). With bulky substituents such as t-butyl and hexyl at the benzene
ring, the reactions become somewhat slower, but excellent yields can still be achieved in 30
min (6 and 7). This can be because of the effects of the pore size on diffusion or formation of
the species (including intermediates and transition states) involved in the reactions. Aliphatic
terminal alkynes can also give good yield if the reaction time is prolonged (8). Because the
mechanism of A3 coupling involves deprotonation of the terminal C-H group, the lower
reactivity of aliphatic alkynes can be due to their weaker acidity relative to aromatic ones, as
indicated by pKa values (for example, pKa = 27.4 for propyne, while pKa = 22.6 for
phenylacetylene [43]). The catalyst is also applicable to different secondary amines, which
serve as bases to help deprotonation of alkynes. Morpholine (pKa = 8.49 for the
corresponding ammonium cation) and diethylamine (pKa = 10.80) are less basic than
piperidine (pKa = 11.12) [43] and hence less reactive for the A3 coupling with
phenylacetylene and paraformaldehyde (9 and 10). Nevertheless, prolonged reactions (2-7 h)
could lead to good yields. The reaction rate also declined if paraformaldehyde was replaced
14

by other aliphatic aldehydes, but modest to good yields can still be achieved by prolonged
reactions (11-13, Scheme 2).
Scheme 2. Catalytic data for A3 coupling of various substrates. The yields were calculated via 1H NMR.
For 4 and 5, 2 ml toluene was used to dissolve the solid alkyne. Compounds 14b and 15b are the
by-products appearing with the corresponding A3-coupling products (14a and 15a, respectively).
When benzaldehyde was used, a conversion of 98% was reached after 4 h, and the yield of
the propargylamine product (14a) is 85%, with chalcone (14b) as byproduct (13%). A
prolonged reaction led to the conversion from 14a to 14b. The coupling reaction with
15

p-fluorobenzaldehyde also afforded an excellent conversion (15a), with a smaller amount of
the enone byproduct (15b). p-Methylbenzaldehyde shows a lower conversion to
propargylamine (16), with no enone byproduct in 4 h, which however can be formed after
prolonged time. The formation of enones from aromatic aldehydes, alkynes and amines has
recently been recognized as a Cu- or Ag-catalyzed secondary reaction following the formation
of propargylamines [30, 44]. No enone byproduct was not observed in the reactions using
aliphatic aldehydes. The different reactivity of aromatic aldehydes compared with aliphatic
ones is because the benzylic-type tertiary C-H group in the propargylamine products (for
example, 14a) derived from aromatic aldehydes has high acidity in favor of
propargyl-to-allenyl isomerization [30, 44].
3.3 Cascade A3 coupling and cyclization over MIL-101-SO3Cu
Propargylamines are versatile precursors to N-containing heterocycles. An example is the
indole motif, which is distributed in a wide variety of natural products and pharmaceuticals
[45]. There have been intriguing protocols that using one-pot tandem A3 coupling and
cyclization reactions to synthesize indole derivatives [46, 47]. To expand the utility of
MIL-101-SO3Cu, the one-pot reactions combining A3 coupling and 5-endo-dig cyclization
were performed using N-protected ethynylaniline, paraformaldehyde and piperidine. As
shown in Table 3 (entry 1), the one-pot catalytic reaction at 60 C under solvent-free
conditions led to complete conversion of Ts-protected-2-ethynylaniline (I) in 0.5 h. However,
product analysis indicated that the yield of the target product (IV) was only 34%. No
propargylamine intermediate was detected, and the remaining product was confirmed by
NMR to be an N-protected indole (V). The undesired product obviously arises from
intramolecular cycloaddition of I, which competes with and dominates over the cascade
A3-cyclization reaction under the conditions used.
16

Table 3. Optimization study for tandem A3 coupling and cyclization reactions over MIL-101-SO3Cua
Entry
Reactant
Solvent (ml)b
T (⁰ C)
t (h)
Yield (%)
IV
V
65
35
0
1
2c
3
I+II+ III
I+III
-
60
60
60
60
60
60
60
60
60
60
60
80
0.5
2.5
2.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
34
0
EA (0.4 )
EA (0.4 )
0
I
4
I+III
EA (0.4 )
CHCl3 (0.4 )
DMF (0.4 )
MeOH (0.4 )
acetone (0.4)
EA (0.4 )
EA (1.0 )
EA (2.0 )
EA (1.0 )
0
73
39
77
44
14
7
5
I+II+ III
I+II+ III
I+II+ III
I+II+ III
I+II+ III
I+II+ III
I+II+ III
I+II+ III
26
22
55
85
92
97
97
86
6
7
8
9
10
11
12
2
2
13
1
a Reactants: I (1.0 mmol), II (1.3 mmol), III (1.0 mmol); catalyst: 24 mg. Yields were calculated via H
NMR of the crude reaction mixture. b EA = ethyl acetate, DMF = N,N'-dimethylformide. c Without the solid
catalyst.
The intramolecular cycloaddition is known to be catalyzed by some metal catalysts [48, 49]
but has not been recognized in previous studies of A3 coupling. Control tests indicated that I
alone cannot undergo the intramolecular reaction, and the reaction proceeds slowly in the
presence of piperidine (entry 2, Table 3). MIL-101-SO3Cu alone cannot catalyze the reaction
(entry 3) but can significantly accelerate the reaction in the presence of amine (entry 4). These
17

results justify the formation of V under the A3 coupling conditions. Considering that the high
concentration of piperidine under solvent-free conditions could favor V more than IV, we
have performed optimization experiments using different types and amount of solvents to
maximize the yield of IV. As can be seen from Table 3, CHCl3 is not a good solvent for both
reactions (entry 5), DMF is in favor of the intramolecular cycloaddition (entry 6), and MeOH
gives comparable selectivities for the two products (entry 7). Acetone affords a good
selectivity for IV, while an excellent selectivity is achieved in ethyl acetate (entries 8 and 9).
The selectivity can be further improved if using more ethyl acetate (entries 9-11). The
reaction at the higher temperature gives a lower selectivity for IV (entry 12). Under the
optimized conditions (entries 10 and 11, Table 3), the yield and selectivity of IV can reach 97 %
in 30 min. The TOF is about 200 h-1, which is much higher than those (less than 70 h-1) for the
same cascade reaction over different Au and Cu catalysts [35, 47]. The high catalytic
efficiency of MIL-101-SO3Cu for the cascade reaction could also arise from the structural
features outlined above.
4. Conclusions
In summary, we have developed an efficient MOF-supported Cu catalyst for A3 coupling,
which features facile preparative and catalytic procedures (solvent-free and air-resistant),
good recyclability, and most importantly, extremely high activity, with the highest TOF
(6.8105 h-1) so far reported for the reaction. The high activity can be related to the single-site
metal dispersion and unhindered open metal environments enabled by the structure of the
supporting MOF. The catalyst is also very efficient for the preparation of indole derivatives
through tandem A3 coupling and cyclization reactions. This work not only indicates
MIL-101-SO3Cu to be a promising catalyst for applications, but also demonstrates MIL-101
as a simple and nice platform for the development of highly active earth-abundant metal
catalysts that are desired for sustainable chemical synthesis.
Acknowledgements
18

This work is supported by the National Natural Science Foundation of China (Grant No.
21471057 and 21773070).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/xxxx.
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