Diastereoselective Synthesis of Pyranoquinolines on Zirconium-Containing UiO-66 Metal-Organic Frameworks

Article abstract of DOI:10.1002/ejic.201600372

The Zr terephthalate MOFs UiO-66 and UiO-66-NH₂have been found to be highly diastereoselective catalysts for the synthesis of a pyrano[3,2-c]quinoline through an inverse electron-demand aza-Diels–Alder [4+2] cycloaddition of an aryl imine (form

Full text of DOI:10.1002/ejic.201600372

DOI: 10.1002/ejic.201600372
Full Paper
Zr MOF Catalysts
Diastereoselective Synthesis of Pyranoquinolines on Zirconium-
Containing UiO-66 Metal-Organic Frameworks
Víctor L. Rechac,[a] Francisco G. Cirujano,[a] Avelino Corma*[a] and
Francesc X. Llabrés i Xamena*[a]
Abstract: The Zr terephthalate MOFs UiO-66 and UiO-66-NH2 dihydro-2H-pyran in one pot, affording the corresponding trans
have been found to be highly diastereoselective catalysts for isomer in diastereomeric excesses of 90–95 %. The solids are
the synthesis of a pyrano[3,2-c]quinoline through an inverse stable under the reaction conditions and can be reused at least
electron-demand aza-Diels–Alder [4+2] cycloaddition of an aryl three times without significant loss of activity or diastereo-
imine (formed in situ from aniline and benzaldehyde) and 3,4- selectivity.
Introduction
pared by using bifunctional heterogeneous catalysts based on
Pd or Pt species encapsulated inside Cr-MIL-101 MOFs through
a tandem nitroarene reduction and intramolecular reductive
amination of nitrocinamaldehyde.[16] Nonetheless, one of the
most important synthetic routes for preparing six-membered
nitrogen heterocycles including (tetrahydro)quinolines is the
so-called Povarov reaction.[17] This reaction consists of an in-
verse electron-demand aza-Diels–Alder [4+2] cycloaddition of
an aryl imine (formed in situ from aniline and an aldehyde)
and electron-rich alkenes. In particular, by using 3,4-dihydro-
2H-pyran (hereafter DHP) as the electron-rich dienophile, the
corresponding PQ can be obtained, usually as a pair of cis and
trans diastereoisomers, the ratio depending on the synthesis
conditions used (Scheme 1).
Various homogeneous and heterogeneous acid catalysts, in-
cluding SnCl2,[18] SbCl3 doped on hydroxyapatite (SbCl3-
HPA),[19] tungstophosphoric acid supported on nanosized MCM-
41 (TPA/MCM-41),[20] perchloric acid adsorbed on silica gel
(HClO4-SiO2),[21] GdCl3,[22] and ferric sulfate,[23] have been re-
ported for the synthesis of tetrahydropyranoquinolines. How-
ever, some of the methods used so far suffer from limitations
such as the use of large amounts of catalyst (up to 50 mol-%),
very low diastereoselectivities, or poor catalyst reusability.
Herein we will show that Zr-containing MOFs bearing acid sites
can be efficiently used as recoverable heterogeneous acid cata-
lysts for the synthesis of PQs, affording high activities and excel-
lent diastereoselectivities towards the trans (exo) isomer 6. In
reports of research related to the present work, some authors
have indeed demonstrated that various MOFs bearing acid
functionalities can catalyze the Diels–Alder reactions (both nor-
mal and inverse-demand) of various substrates.[24–29]
Metal-organic frameworks (MOFs) are crystalline porous materi-
als constructed of metal ions or metal oxo clusters connected
by multitopic organic ligands into extended one-, two-, or
three-dimensional frameworks. Their strictly regular and tun-
able porous systems and huge surface areas of thousands of
square meters per gram, together with the possibility of intro-
ducing different functionalities at the metal nodes and organic
linkers or inside the pores (either by direct synthesis or through
post-synthetic modification of pre-formed MOFs) make them
very promising candidates for applications in, for example, gas
separation[1–3] and heterogeneous catalysis.[4–7] In particular,
the high tunability of the composition, structure, and intra-cav-
ity chemical environment of MOFs are invaluable for the design
and synthesis of highly chemo-, regio-, and enantioselective
MOFs for use as catalysts for the synthesis of high-added-value
chemicals.
Tetrahydroquinoline derivatives are an important class of
heterocyclic compounds with a wide variety of biological activi-
ties, such as anti-allergic,[8] anti-inflammatory,[9] anti-arrhyth-
mic,[10] anti-malarial,[11] anti-tumor,[12] and anti-oxidant activ-
ity.[13] Among them, pyrano[3,2-c]quinolines (hereafter PQs)
form the core of various natural bioactive alkaloids, such as
simulenoline, huajiaosimuline, flindersine, veprisine, and ori-
cine.[14,15] In our ongoing research into the application of metal-
organic frameworks (MOFs) as heterogeneous catalysts for the
synthesis of high-added-value chemicals, we have recently re-
ported that (tetrahydro)quinoline derivatives can be readily pre-
[a] Instituto de Tecnología Química, Universitat Politècnica de València,
Consejo Superior de Investigaciones Científicas,
Avenida de los Naranjos s/n, 46022 Valencia, Spain
E-mail: acorma@itq.upv.es
In the present work we used Zr-containing MOFs of the UiO-
66 type to catalyze the synthesis of a PQ. These MOFs belong
to a highly robust family of compounds formed by Zr6 hexam-
eric oxo-aggregate units connected by 12 linear dicarboxylate
molecules in close-cubic packing that define octahedral and
tetrahedral pores, both of which are accessible through triangu-
fllabres@itq.upv.es
http://itq.upv-csic.es/en
http://personales.upv.es/fllabres
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejic.201600372.
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Scheme 1.
lar windows with free openings of about 6 Å (in the case of product (below 5 % yield) was also detected, which was identi-
UiO-66 with terephthalate linkers), as shown schematically in fied as the aza-Michael addition product of aniline and DHP.
Figure 1.[30] However, this ideal structure of UiO-66-type MOFs When acetonitrile was replaced by other solvents, either polar
is frequently interrupted by the occurrence of defects, mainly (ethanol, N,N-dimethylformamide) or apolar (toluene, hexane,
associated with linker deficiencies, that leads to a connectivity chloroform), the final yield of the PQ product was considerably
of the Zr6 units lower than the expected value of 12 and to lower or even negligible. As expected, no PQ was obtained in
the formation of Zr4+ ions having coordinative unsaturation.[31] the absence of catalyst. Table 1 summarizes the results obtained
There is now clear evidence that coordinatively unsaturated with various MOFs and other acid catalysts taken from the liter-
Zr4+ sites associated with defects are mainly responsible for the ature for comparison.
well-known acidic character of these compounds, as has already
been shown for a number of acid-catalyzed reactions.[32–35]
Figure 1. Pictorial view of the UiO-66 MOF structure showing the Zr6 oxo-
aggregates (left) and their close-cubic packing (center) to form octahedral
and tetrahedral cavities (right), both of which are accessible through triangu-
lar faces (evidenced by bold lines).
Figure 2. Conversion of aniline 1 on UiO-66 (■) and evolution of the products:
intermediate imine 3 (▲) and PQs 5 and 6 ().
According to the XRD and ICP-OES analyses of the solid cata-
lyst recovered after the reaction (see Figure S1 in the Support-
ing Information), UiO-66 was found to be stable under the reac-
Results and Discussion
tion conditions and was reusable for at least three catalytic
cycles without significant loss of activity or diastereoselectivity
Synthesis of PQs Over Zr-MOFs
(Table 1, entries 1–3).
When an acetonitrile solution of aniline, benzaldehyde, and
DHP was placed in contact with Zr-containing UiO-66-type
Compared with UiO-66, UiO-66-NH2 afforded slightly better
MOFs (3.6 mol-% Zr with respect to aniline), the imine interme- results in terms of PQ yield in a shorter reaction time (Table 1,
diate 3 was immediately obtained, which was gradually con- entry 4 and Figure S3 in Supporting Information), as well as
verted into the desired cis and trans PQs 5 and 6, respectively. affording an excellent diastereomeric ratio. UiO-66-NH2 was also
As an example, Figure 2 shows the kinetic evolution of products found to be stable and reusable without loss of activity under
obtained when UiO-66 was used as the catalyst. Thus, after 22 h the reaction conditions. In comparison, ZrCl4 (entry 7) was
of reaction time, the final yield of the PQ obtained was 83 % found to be much more active for the aza-Diels–Alder reaction
with an excellent diastereoselectivity; the trans/cis diastereo- than both Zr-MOFs, yielding 85 % PQ in only 15 min under the
1
meric excess (de) was 94 % (as determined by H NMR spectro- same reaction conditions. However, the product was obtained
scopy). Besides PQ and the intermediate imine, a minor side- as a mixture of trans and cis isomers in a ratio of 73:27, which
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Table 1. Synthesis of PQs over various solid acid catalysts.[a]
pect much smaller differences in the catalytic activities of the
samples with 45 and 60 nm particles, of around 33 %. Therefore,
the higher activity of the sample with the smallest particles
probably reflects a higher number of defects (in the form of
linker deficiencies) located at the external surface compared
with the sample with particles of 60 nm. It is worth mentioning
that thermogravimetric analysis of the samples can provide an
estimation of the overall number of linker defects (both internal
and external) following the method proposed by Valenzano et
al.[31] Therefore, because we did not observe significant differ-
ences in the total amounts of defects in these two samples (ca.
8 % in both cases), our catalytic results suggest that these de-
fects are not equally distributed among the internal and exter-
nal surfaces of the MOFs from one sample to another (see
Table S1 in the Supporting Information and the discussion
therein).
Catalyst
[Cat.]
[mol-%]
Time [h]
Yield of PQ
[mol-%]
de[b][%]
1
2
3
4
5
6
7
8
UiO-66
3.8
3.8
3.8
3.8
3.8
3.8
3.8
3.8
3.8
3.8
10
1.6
0.5
5
25
10
10
20
20
20
50
10 (22)
22
22
3 (10)
3 (22)
22
0.25
24
24
24
1.8
2.5
2.25
0.25
12
1.5
0.5
5
0.5
1.5
2
75 (83)
77
75
74 (88)
32 (77)
<5
85
<5
<5
<5
95
85
88
95
84
87
85
88
94
92
91
88
90
–
46
–
–
UiO-66 1st reuse
UiO-66 2nd reuse
UiO-66-NH2 (45 nm)
UiO-66-NH2 (60 nm)
UiO-66-NH2 (130 nm)
ZrCl4
(Cr)-MIL-101
9
(Al)-MIL-101-NH2
(Fe)-MIL-101-NH2
SnCl2·2H2O[18]
SbCl3-HAP,[19][c]
TPA/MCM-41[20]
10
11
12
13
14
15
16
17
18
19
20
21
–
40
100
16
78
22
56
90
46
18
70
58
[21]
HClO4-SiO2
[22]
GdCl3
Fe2(SO4)3·xH2O,[23][c]
To circumvent the limitations of product diffusion when nar-
row-pore Zr-MOFs were used as catalysts, we turned our atten-
tion to metal-organic compounds with pores in the mesopo-
[36]
NbCl5
[37]
[38]
[39]
SmI2
InCl3
LiBF4
80
88
76
rous range. In particular, we considered trivalent metal (Fe3+
,
[40]
CuBr2
Cr3+, and Al3+) terephthalates of the MIL-101 family. This is a
family of highly robust compounds featuring mesoporous cavi-
ties (ca. 3–3.5 nm) accessible through pentagonal and hexago-
nal windows of 1.2–1.5 nm, which are large enough to allow
diffusion of very large molecules. Moreover, these materials are
known to exhibit Lewis acid properties arising from coordina-
tive unsaturation of the trivalent cations in the MIL-101struc-
ture, which, in principle, could also catalyze the Povarov reac-
tion leading to PQs. However, when these MIL-101 materials
were used as catalysts, there was hardly any formation of PQ
(maximum yields below 5–10 %) under the mild reaction condi-
tions used (room temperature and only 3.8 mol-% M3+ with
respect to aniline). This result probably reflects the lower polar-
[a] Reaction conditions with the Zr-MOF catalysts: Aniline (1 mmol), benzalde-
hyde (1.2 mmol), DHP (2 mmol), acetonitrile (0.5 mL), Zr-MOF (3.8 mol-% Zr),
r.t.. [b] Diastereomeric excess: [(trans – cis)/(trans + cis)] × 100. [c] The reaction
was carried out by heating at reflux in acetonitrile.
corresponds to a considerably lower diastereomeric excess of
only 46 %.
To put into context the results obtained with the Zr-MOFs,
we also compared our catalytic results with other solid catalysts
described in the literature. In particular, concerning the dia-
stereoselectivity, the results obtained with the Zr-MOFs rivaled
those obtained with NbCl5 and HClO4-SiO2, and were clearly
surpassed only by SbCl3-HAP (Table 1, entry 12). However, with
these exceptions, Zr-MOFs largely outperformed most of the
solid acid catalysts reported so far in the literature. Altogether,
considering their good activity, excellent diastereoselectivity,
and easy reusability, the Zr-containing MOFs studied in the
present work emerge as convenient and reusable solid acid cat-
alysts for the synthesis of PQs from amine, aldehyde, and DHP
in one pot at room temperature with excellent diastereoselect-
ivity.
Considering the dimensions of the PQs relative to the pore
openings of the Zr-MOFs, it is evident that the Povarov three-
component coupling reaction can only take place at the exter-
nal surface of the solid catalyst. In agreement with this, three
different UiO-66-NH2 samples with particle sizes ranging from
45 to 130 nm (see Figure S2 in the Supporting Information)
showed significant differences in catalytic activity, which de-
creased with increasing particle size, as expected. Thus, the
turnover frequency (TOF) for the formation of PQ calculated
after 3 h of reaction was 6.5 h–1 for the sample with the smallest
particles (45 nm). This value was reduced to less than half when
we used a sample containing particles with an average size of
izing power (Z2/r ratio) and thus the lower Lewis acidity of Fe3+
,
Cr3+, and Al3+ cations with respect to the Zr4+ ions present in
the UiO-66-type compounds. Therefore, in the light of our cata-
lytic results, Zr4+ ions (with coordinative unsaturation due to
ligand defects in the structure[33]) are strong enough acids to
activate the intermediate imine, thus increasing the electro-
philic character of the carbonyl carbon (coming from benzalde-
hyde) and facilitating the attack of the electron-rich DHP dieno-
phile. In contrast, the M3+ ions in MIL-101 would not be capable
of activating the intermediate imine enough to trigger the
Diels–Alder cycloaddition at room temperature.
Proposed Mechanism
The Povarov reaction leading to PQs is actually a domino two-
step reaction consisting of an aza-Diels–Alder [4+2] cycloaddi-
tion (aza-D–A) followed by a tautomeric 1,3-hydrogen shift to
yield the final tetrahydroquinoline molecule in which the aro-
matic ring is regenerated (Scheme 2).
There is still some controversy over the mechanism of the
60 nm (2.8 h–1), whereas a UiO-66-NH2 sample with particles of aza-D–A reaction, as to whether it is a concerted or a stepwise
130 nm was almost inactive for the formation of PQ (compare reaction.[36,41,42] It is generally accepted that the use of strong
entries 4–6 in Table 1). If only simple geometric considerations electrophilically activated azadienes and strong nucleophilically
(surface-to-volume ratio) are taken into account, one would ex- activated ethylenes favors a two-step reaction. Activation of the
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a “macroligand” of the Zr ions, which would explain the high
diastereomeric selectivity observed. A similar mechanism has
been proposed by da Silva et al. to explain the diastereoselect-
ivity of the NbCl5-catalyzed Povarov reaction,[36] and steric hin-
drance has also been claimed to be the factor influencing the
outcome of a reaction by controlling the orientation of its inter-
mediates.[43]
Scheme 2.
Once the aza-D–A product has been formed, the ensuing
1,3-hydrogen shift reaction takes place leading to the final PQ
product. Again, this reaction can be considered either a con-
certed or a stepwise process. However, the direct (concerted)
1,3-hydrogen shift is very unfavorable due to the formation of
a very strained four-membered transition state.[41] Given the
acidic character of the hydrogen atom involved in the tautom-
erization, the presence of a basic species or protic solvents
(such as water) is expected to accelerate the reaction. Therefore,
the presence of amino groups in UiO-66-NH2 may be responsi-
ble for the higher catalytic activity observed for this catalyst
compared with UiO-66 by either participating directly in the
tautomerization reaction or by favoring the adsorption of water
generated during the formation of imine in close proximity to
the Zr catalytic sites. In this sense, it has been reported by
Walton and co-workers that amino groups in the terephthalate
linkers indeed favor water adsorption on the material.[44]
azadiene can either be achieved by protonation of the imine
by Brønsted acids or by the coordination of the N atom to
strong Lewis acids, whereas the presence of electron-releasing
groups in the ethylene increases its nucleophilic character. The
first step consists of the nucleophilic attack of C6 of the ethyl-
ene on C1 of the imine (the attack on C4 being energetically
very unfavorable). The formation of this C1–C6 single bond can
take place from two approaching directions (endo and exo),
which will eventually determine the formation of either the cis
or trans PQ isomer. The second step of the aza-D–A reaction
consists of the ring-closing reaction with the formation of the
C4–C5 single bond.
In the particular case of the Povarov reaction catalyzed by
Zr-MOF, the following mechanism can be hypothesized
(Scheme 3). In the first step, the in situ formed imine is coordi-
nated to the coordinatively unsaturated Zr ions of the MOF,
most probably associated with missing linker defects. This coor-
dination activates the electrophilic character of the imine,
thereby favoring nucleophilic attack by DHP. The presence of
bulky substituents in the Lewis acid coordinated to the imine
can introduce important steric hindrance, which would favor
the formation of the trans isomer through the exo approach of
the DHP molecule. In this sense, the MOF can be considered as
Conclusions
In this work we have shown that UiO-66-type metal-organic
frameworks containing coordinatively unsaturated Zr4+ ions as-
sociated with linker vacancies are highly diastereoselective
heterogeneous catalysts for the inverse electron-demand
hetero-Diels–Alder cycloaddition (Povarov reaction) of an imine
and DHP leading to a trans-pyrano[3,2-c]quinoline with dia-
stereomeric excesses of around 90–95 %. This diastereoselectiv-
ity clearly outperforms most of the solid Lewis acid catalysts
reported so far, with the sole exception of SbCl3-HAP.[19] Both,
UiO-66 and UiO-66-NH2 compounds, prepared with terephthalic
and aminoterephthalic ligands, respectively, are stable under
the very mild reactions conditions used (room temperature)
and can be reused at least three times without significant loss
of activity or diastereoselectivity.
The relatively small pores of UiO-66 materials with respect
to the dimensions of PQs prevent the reaction from occurring
inside the pores of the MOFs, so only the active centers located
at the external surface of the particles contribute to the ob-
served activity. Accordingly, as the average particle size of UiO-
66-NH2 increases from 45–60 nm, the calculated TOFs decrease
from 6.5–2.8 h–1.
Experimental Section
Synthesis of UiO-66 and UiO-66-NH2: All syntheses were per-
formed according to the procedure reported by Kandiah et al.[45]
Briefly, ZrCl4 (750 mg) and either terephthalic acid (740 mg; UiO-
66) or aminoterephthalic acid (800 mg; UiO-66-NH2) were dissolved
in DMF (90 mL; Zr/ligand/DMF molar ratio of 1:1:220) and the solu-
tion was kept in a closed round-bottomed flask in an oil bath at
Scheme 3.
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The resulting materials were recovered by filtration and washed
thoroughly with fresh DMF. Then the solids were washed three
times by soaking them in dichloromethane for 3 h. Finally, the solid
was recovered by filtration and dried under vacuum at room tem-
perature. X-ray diffraction (Phillips X′Pert, Cu-Kα radiation) was used
to confirm the expected structure type and high crystallinity of the
materials.
Catalytic Studies: In a typical catalytic reaction, aniline (93 mg,
1 mmol), benzaldehyde (127 mg, 1.2 mmol), and 3,4-dihydro-2H-
pyran (168 mg, 2 mmol) in acetonitrile (0.5 mL) were added at room
temperature to the MOF (3.6 mol-% Zr with respect to aniline) in a
3 mL batch reactor with a magnetic stirrer. The progress of the
reaction was monitored by GC (Varian 3900 with 30 m × 0.25 mm
BS5-SGE column) and GC–MS (Agilent 6890 with 30 m × 0.25 mm
HP-5 column and Agilent mass selective detector 5973) using do-
decane as internal standard. After each cycle, the solid catalysts
were recovered by centrifugation and Soxhlet-washed overnight
with acetonitrile and dried at 60 °C before reuse. The crystallinity
of the recovered material was determined by XRD and compared
with that of the fresh material. The diastereoisomeric excesses of
the products were determined by 1H NMR spectroscopy (Variant
Unity 300 Plus Gemini at 300 MHz, in CDCl3) from the integrated
intensities of the peaks at δ = 3.65 ppm (td, J = 11.5, 2.5 Hz, 1 H)
for the trans isomer and at δ = 3.36 (td, J = 11.3, 2.9 Hz, 1 H) and
5.33 ppm (d, J = 5.6 Hz, 1 H) for the cis isomer in the 1H NMR
spectra of the crude reaction mixtures.
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Acknowledgments
Financial support from the Generalitat Valenciana (projects Con-
solider-Ingenio MULTICAT and AICO/2015/065), the Spanish
Ministry of Economy and Competitiveness (MINECO) (program
Severo Ochoa SEV20120267), and the Spanish Ministry of Sci-
ence and Innovation (MICINN) (project MAT2014-52085-C2-1-P)
is gratefully acknowledged. V. L. R. thanks the Fundación “La
Caixa” for a “La Caixa-Severo Ochoa” Ph. D. Scholarship. This
project received funding from the European Union's Horizon
2020 Tesearch and Innovation Programme under the Marie
Skolodowska Curie grant agreement number 641887.
Keywords: Metal-organic frameworks · Heterogeneous
catalysis · Zirconium · Diastereoselectivity · Cycloaddition ·
Nitrogen heterocycles
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Received: March 31, 2016
Published Online: ■
Eur. J. Inorg. Chem. 0000, 0–0
www.eurjic.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Zr MOF Catalysts
Zirconium-containing
UiO-66-type
compounds catalyze the Povarov reac-
tion between an imine and dihydro-
pyran at room temperature to give
trans-pyrano[3,2-c]quinoline with dia-
stereomeric excesses of 90–95 %. The
solids are stable and reusable catalysts
that show no significant loss of activity
or diastereoselectivity.
V. L. Rechac, F. G. Cirujano, A. Corma,*
F. X. Llabrés i Xamena* .................... 1–7
Diastereoselective Synthesis of Pyr-
anoquinolines on Zirconium-Con-
taining
UiO-66
Metal-Organic
Frameworks
DOI: 10.1002/ejic.201600372
Eur. J. Inorg. Chem. 0000, 0–0
www.eurjic.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim