An efficient and recyclable 3D printed α-Al2O3 catalyst for the multicomponent assembly of bioactive heterocycles

Article abstract of DOI:10.1016/j.apcata.2016.11.031

A catalytic methodology is reported that enables the efficient, operationally simple and environmentally friendly synthesis of diverse 1,4-dihydropyridines and 3,4-dihydropyrimidin-2(1H)-ones, including some relevant drugs and pharmacologically active derivatives. This strategy is based on the use of a 3D printed Al₂O₃ woodpile material that was sintered to generate a rigid structure with controlled porosity and noteworthy catalytic performance. The 3D printed Al₂O₃ catalyst exhibits remarkable efficacy as a Lewis acid in Biginelli and Hantzsch reactions and it can be recovered and reused ten times without any decrease in the activity. Remarkable E factors, excellent recyclability and scalability, broad substrate scope, short reaction times, excellent yields, solvent-free conditions and easy isolation procedures are key features of this methodology.

Full text of DOI:10.1016/j.apcata.2016.11.031

Accepted Manuscript
Title: An Efficient and Recyclable 3D Printed ␣-Al O3
2
Catalyst for the Multicomponent Assembly of Bioactive
Heterocycles
Author: Jhonny Azuaje Carmen R. Tub ´ı o Luz Escalante
M o´ nica G o´ mez Francisco Guiti a´ n Alberto Coelho Olga
Caama n˜ o Alvaro Gil Eddy Sotelo
PII:
S0926-860X(16)30570-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2016.11.031
APCATA 16079
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
26-8-2016
21-11-2016
24-11-2016
Please cite this article as: Jhonny Azuaje, Carmen R.Tub ´ı o, Luz Escalante,
M o´ nica G o´ mez, Francisco Guiti a´ n, Alberto Coelho, Olga Caama n˜ o, Alvaro Gil,
Eddy Sotelo, An Efficient and Recyclable 3D Printed ␣-Al2O3 Catalyst for the
Multicomponent Assembly of Bioactive Heterocycles, Applied Catalysis A, General
http://dx.doi.org/10.1016/j.apcata.2016.11.031
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An Efficient and Recyclable 3D Printed α-Al
2
O Catalyst for the
3
Multicomponent Assembly of Bioactive Heterocycles
Jhonny Azuaje,a,b,d Carmen R. Tubío, Luz Escalante, Mónica Gómez, Francisco Guitián,
c
a,b
c
c
Alberto Coelho,a,b,d Olga Caamaño,b,d Alvaro Gil, * and Eddy Soteloa,b,d,*
c,
aCentro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS),
Universidade de Santiago de Compostela, E-15782, Santiago de Compostela, Spain.
bDepartamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de
Compostela, E-15782, Santiago de Compostela, Spain.
cInstituto de Cerámica, Universidade de Santiago de Compostela, E-15782, Santiago de
Compostela, Spain.
dInstituto de Farmacia Industrial (IFI), Universidade de Santiago de Compostela, E-15782
Santiago de Compostela, Spain
*
Corresponding authors:
E-mail addresses: alvaro.gil@usc.es (A. Gil), e.sotelo@usc.es (E. Sotelo)
Graphical abstract
1

Highlights
1
2
. An Al
2
O
3
woodpile structure is prepared via 3D printing and subsequent sintering.
. The 3D printed Al
2
O catalyst exhibits remarkable efficacy as a Lewis acid in
3
Biginelli and Hantzsch reactions and it can be recovered and reused without any
decrease in the activity.
3
. The optimised protocols enable the efficient, operationally simple and
environmentally friendly synthesis of diverse 1,4-dihydropyridines and 3,4-
dihydropyrimidin-2(1H)-ones.
Abstract
A catalytic methodology is reported that enables the efficient, operationally simple
and environmentally friendly synthesis of diverse 1,4-dihydropyridines and 3,4-
dihydropyrimidin-2(1H)-ones, including some relevant drugs and pharmacologically active
derivatives. This strategy is based on the use of a 3D printed Al
was sintered to generate a rigid structure with controlled porosity and noteworthy catalytic
performance. The 3D printed Al catalyst exhibits remarkable efficacy as a Lewis acid in
2
O
3
woodpile material that
2
O
3
Biginelli and Hantzsch reactions and it can be recovered and reused ten times without any
decrease in the activity. Remarkable E factors, excellent recyclability and scalability, broad
substrate scope, short reaction times, excellent yields, solvent-free conditions and easy
isolation procedures are key features of this methodology.
Key words: 3D Printing, Al
2
3
O , Multicomponent reactions, 1,4-Dihydropyrimidines,
3
,4-Dihydropyrimidin-2(1H)-ones
2

1
. Introduction
Nitrogen-based heterocyclic compounds are featured in a plethora of naturally
occurring compounds, pharmacologically active substances, agrochemicals and therapeutic
agents, therefore they are valuable frameworks in drug discovery [1,2]. Of these heterocycles
1
,4-dihydropyridines [3-6] and 3,4-dihydropyrimidin-2(1H)-ones [3,7-9] have emerged as
prolific chemotypes that elicit significant biological activities (Scheme 1) [10,11], thus
embodying the archetype of privileged scaffolds [12]. In addition to bioactivity issues, the
versatility of a privileged scaffold is heavily dependent on the synthetic feasibility. The
implementation of concise and efficient synthetic methodologies to target these heterocyclic
cores is therefore a highly desirable goal within the competitive environment of drug
discovery. The increasing ecological concerns of modern society mean that contemporary
chemists have the challenge of developing environmentally friendly preparative methods [13-
1
5]. In this context, multicomponent reactions (MCR) [16-18] have gained increasing
importance within the toolbox of sustainable synthetic methodologies [19]. In addition to
encompassing major principles of organic synthesis (e.g., convergence, efficiency, selectivity
and atom and step economies), recent reports exemplify progressive efforts to increase the
adherence of MCR to most of the green chemistry principles [20-22].
The Hantzsch [23] and Biginelli [24,25] multicomponent reactions are the standard
synthetic transformations to assemble 1,4-dihydropyridines and 3,4-dihydropyrimidin-2(1H)-
ones, respectively. Both reactions have proven to be markedly affected by the presence of
catalysts or additives [5,26-28], which modify the reaction outcome not only from the
quantitative but also from the qualitative point of view. Inspired by the pharmacogenicity of
these scaffolds, a plethora of catalysts have been developed for both transformations within
the last twenty years [5,26-28]. The currently used protocols for the Hantzsch and Biginelli
3

condensations provide transformations that are considered to be efficient by traditional
chemistry paradigms, but the green chemistry perspective is considerably broader [20-22]
and, in addition to yield, selectivity and number of steps, criteria for waste generation, use of
reagents and solvents, use of hazardous chemicals, energy intensity and general safety are
considered. Existing procedures for these transformations generally suffer from significant
drawbacks in terms of environmental impact [5,19,26-28]. The utilization of variable amounts
of non-reusable Lewis or Brønsted acids [5,26-28] or toxic transition-metals catalysts are of
particular concern [5,26-28], but also the use of non-recyclable non-biodegradable solvents
and waste generation. Moreover, most available procedures are not amenable to
miniaturization and parallelization, thus hindering the implementation of high-throughput
synthetic methodologies.
In the context of a programme aimed at developing environmentally friendly
heterogeneous catalytic systems to enable high-throughput synthetic methodologies for the
generation of bioactive heterocyclic libraries [29,30], we focused on the synthesis of 3,4-
dihydropyrimidin-2(1H)-one and 1,4-dihydropyridine libraries as adenosine receptor
antagonists [31,32]. Encouraged by the excellent results obtained on using Lewis acids [5,26-
2
8] as catalysts for Hantzsch and Biginelli multicomponent reactions, we envisioned the
development of a greener alternative for rapid library generation using a recyclable 3D
printed alumina catalyst.
Aluminium-based Lewis acids are widely employed as catalysts and co-catalysts in
organic synthesis [33] and it has been claimed that some of them are efficient catalysts for
Hantzsch and Biginelli reactions [34-37]. In addition to their diverse applications [33], the
hygroscopic nature and reactivity of aluminium-based Lewis acids [38,39], along with the
pyrophoric nature of some of them [40], generally means that stringent experimental
conditions are required, thus making these materials incompatible with several solvents and
reagents. In addition, some studies have highlighted the toxicity of reactive aluminium-based
4

reagents [41-43]. Although the amount of Lewis acid required usually depends on the
transformation (ranging from sub-stoichiometric amounts to excess) it should be noted that
aqueous quenching of the reaction releases aluminium species and other chemical residues
(
ca. 3 equivalents of HCl per equivalent upon neutralization when using AlCl ) [44,45],
3
which could be challenging during the large-scale synthesis of active pharmaceutical
ingredients. Recent examples have emphasised the distinct advantages of solid acids
compared to aluminium-based homogenous Lewis acids [46,47].
The presence of alumina in nature, and its diverse emerging applications, have made
this material increasingly recognized as a valuable renewable resource [48,49]. The innocuous
nature, recyclability and applications of alumina have established it as an efficient and
environmentally friendly alternative to soluble aluminium compounds [50-58]. However, fine
applications critically depend on the surface properties of alumina (e.g., Brønsted acidity or
basicity, Lewis acidity or redox properties of the surface metal ions), which are highly
dependent on the degree of surface hydroxylation [59-63]. In order to generate the desired
surface it is common to perform thermal treatments (e.g., calcination) [64,65] to remove
surface-bound hydroxyl groups within the material or, alternatively, chemical
functionalization of the surface [66-69]. It has been verified that the Lewis acidity of alumina,
which is required for several catalytic applications, is significantly increased by
dehydroxylation of surface-bound hydroxyl groups [59-63]. As for silica and titania, thermal
treatment of alumina promotes condensation between vicinal hydroxyl groups to release
molecular water and form bridged M–O–M linkages (M = Si, Ti or Al) during the process,
thus creating coordinatively unsaturated aluminium ions [70,71]. The mechanism of thermal
dehydroxylation on the alumina surface remains obscure, but it is well documented that
heating at 500 ºC causes a substantial decrease in the number of OH groups [70,71]. Further
heating, to temperatures above 1050 ºC, promotes surface reconstruction with the appearance
5

of more acidic aluminium sites, which in turn strongly affects the surface morphology,
stoichiometry and chemical reactivity [70-72].
In this work a 3D printing approach was employed for first time to synthesise a
reusable alumina catalyst with a high surface/volume ratio and controlled porosity. The 3D
printing technique [73-75] has been established as a powerful method for the fabrication of
complex 3D structures with numerous applications, including photonic crystals [76,77],
electronic components [78], biomaterials [79,80] and catalysis [29]. The technique is based on
a computer-aided design (CAD) that uses the deposition of concentrated inks with specific
viscoelastic properties through a nozzle to build interconnected 3D structures in a layer-by-
layer build sequence. One of the main advantages of the structures fabricated by 3D printing
is the possibility of controlling the architecture as well as the size, pore geometry, and
consequently the surface properties of the material. 3D printed Al
2
O
3
structures with a high
surface area and appropriate morphology can be engineered using this technique, by
employing a highly concentrated aqueous Al
treatment.
2
3
O colloidal ink and subsequent thermal
Faced with the challenge of developing a highly active catalyst that would enable the
optimization of an efficient and environmentally friendly protocol for the synthesis of
bioactive 3,4-dihydropyrimidin-2(1H)-one and 1,4-dihydropyridine libraries, we report here a
novel catalytic system based on a cylindrical woodpile Al
2
O
3
structure assembled by 3D
printing and sintering. The Al structure proposed here constitutes a recyclable rigid device
2
O
3
that exhibits controlled porosity, high mechanical strength and excellent catalytic efficiency.
Accordingly, it constitutes an attractive material for the implementation of high-throughput
synthetic methodologies.
2
. Experimental
2
.1. Catalyst preparation
The Al
2
O
3
colloidal ink (30 vol%) was prepared by mixing 100 g of Al
2
3
O powder
6

(average particle size of 0.5 μm, density of 3.98 g/mL, Almatis GmbH, Germany), 61.16 mL
of DI-water and 1.08 mL of dispersant Darvan 821A (40 wt% solution, R.T. Vanderbilt,
USA). The resulted suspension was ultrasonicated for 30 min (IKA U200S, Germany) to
ensure the uniform dispersion of the Al
2
3
O particles. Then the suspension was centrifuged at
2
500 rpm for 15 min, and 37.46 mL of supernatant was eliminated to set the concentration of
the suspension at the printing conditions (53 vol%). This suspension was then mixed in a
planetary mixer (Thinky ARE-250, Japan) at 2000 rpm for 2 min. Then, 0.13 g (0.13 wt%
based Al
Aldrich) was added, and the suspension mixed again for 2 min and maintained in equilibrium
for 1 h. Afterwards, 0.16 mL (0.17 wt% based on Al ) of polyethylenimine (PEI, M
000, Sigma-Aldrich) was added to the suspension, and the mixture was again mixed several
2
3
O ) of hydroxypropyl methylcellulose (HPMC, viscosity of 2600-5600 cP, Sigma-
2
O
3
W
=
2
times. The catalytic structure was fabricated at room temperature using a robotic deposition
apparatus (Model A3200, Aerotech Inc., USA). The ink was loaded into a 3 mL syringe barrel
(Nordson EFD, Japan) fitted to a cylindrical nozzle (diameter of 410 μm, EFD) and printed at
3
mm/s of printing velocity and 21 bar of pressure using an applied air pressure (Performus
VII attached to HP7x, EFD). The 3D catalytic structure consists of a cylinder lattice of 30
layers and 10 mm of diameter with body-centered tetragonal (bct) symmetry, and a rod
diameter of 410 μm and inter-rod spacing of 960 μm. The structure was built layer by layer,
where each layer was rotated 90° with respect to the previous one. This sequence was
replicated every two layers. After printing, the fabricated structure was dried in air for 24 h,
followed by sintering process at 1500 °C in air for 2.5 h with a heating rate of 10 ºC/min.
2
.2. Catalyst characterization
The crystallinity of the Al
2
3
O catalytic support was evaluated by X-ray diffraction
(XRD) patterns using a diffractometer (Siemens D500, Germany) with CuKα radiation (λ =
0
.15405 nm). The data was recorded in the range of 20–80° (2θ) with a 2θ step size of 0.05°.
The surface morphology of the sintered 3D catalytic structure was measured by scanning
7

electron microscope SEM (JEOL 6400, Japan) and stereomicroscope (SZX12, Olympus,
Japan). The specific surface area measurements of the 3D structure and the Al powder
2
O
3
were performed according to the Brunauer–Emmett–Teller (BET) nitrogen
adsorption/desorption method at 77 K in a Gemini 2360 V2.01 porosimeter (Micromeritics,
USA). All samples were degassed at 300 °C for 2 h before the BET-analysis.
2
.3. Chemistry general
Unless otherwise indicated, all starting materials, reagents and solvents were
purchased and used without further purification. After extraction from aqueous phases, the
organic solvents were dried over anhydrous sodium sulfate. The reactions were monitored by
thin-layer chromatography (TLC) on 2.5 mm Merck silica gel GF 254 strips, and the purified
compounds each showed a single spot; unless stated otherwise, UV light and/or iodine vapour
were used to detect compounds. The Biginelli and Hantzsch reactions were performed in
coated vials on an Anton Paar microwave synthesizer. Filtration and washing protocols for
supported reagents were performed in a 12-channel vacuum manifold. The purity and identity
of all compounds were established by a combination of HPLC, mass spectrometry and NMR
spectroscopy as described below. Purification of isolated products was carried out
recrystallization of the indicated solvent or medium pressure liquid chromatography (MPLC)
on a CombiFlash Companion (Teledyne ISCO) with RediSep pre-packed normal-phase silica
gel (35–60 µm) columns. Melting points were determined on a Gallenkamp melting point
apparatus and are uncorrected. The NMR spectra were recorded on Bruker AM300 and
XM500 spectrometers. Chemical shifts are given as  values against tetramethylsilane as
internal standard and J values are given in Hz. Mass spectra were obtained on a Varian MAT-
7
11 instrument.
2
.4. Representative procedure for the Biginelli synthesis of derivatives 4
8

A mixture of the aldehyde 1 (2 mmol), the 1,3-dicarbonyl compound 2 (2 mmol), the
corresponding urea derivative 3 (3 mmol) and the 3D printed Al structure (0.350 g) was
2
O
3
submitted to microwave irradiation (100º C) in coated vial. After completion of the reaction,
as indicated by TLC, the mixture was cooled and the desired compound solidified. For those
1
,2,3,4-tetrahydropyrimidine-5-carboxylates that not solidified, the reaction mixture was
poured onto crushed ice and stirred for 5–10 min. The solid obtained was filtered under
suction, washed with ice-cold water (20 mL) and then purified by column chromatography or
recrystallization from the appropriate solvent.
2
.5. Representative procedure for the Hantzsch synthesis of derivatives 7 (Method A)
A mixture of the aldehyde 1 (2 mmol), the 1,3-dicarbonyl compound 2 (2 mmol)
ammonium acetate 5 (5 mmol) and the 3D printed Al
2
3
O structure (0.350 g) was submitted to
microwave irradiation (120º C) in coated vial. After completion of the reaction, as indicated
by TLC, the mixture was cooled and the desired compound solidified. For those 1,4-
dihydropyridines that not solidified, the reaction mixture was poured onto crushed ice and
stirred for 5–10 min. The solid obtained was filtered under suction, washed with ice-cold
water (20 mL) and then purified by column chromatography or recrystallization from the
appropriate solvent.
2
.6. Representative procedure for the synthesis of 1,4-dihydropyridines 7 (Method B)
A mixture of the aldehyde 1 (2 mmol), the 1,3-dicarbonyl compound 2 (2 mmol) and
the 3D printed Al
in coated vial. Once the aldehyde component was consumed (TLC control) the corresponding
-aminocrotonate 6 (2 mmol) was added and the mixture heated at 90º C (microwave
2
3
O structure (0.350 g) was submitted to microwave irradiation (120º C) for
3
irradiation). After completion of the reaction, as indicated by TLC, the mixture was cooled
and the desired compound solidified. For those 1,4-dihydropyridines that not solidified, the
reaction mixture was poured onto crushed ice and stirred for 5–10 min. The solid obtained
9

was filtered under suction, washed with ice-cold water (20 mL) and then purified by column
chromatography or recrystallization from the appropriate solvent.
3
. Results and discussion
Al is an excellent material to engineer 3D structures with high mechanical strength
81]. The alumina woodpile structures reported here were assembled by 3D printing of
colloidal Al ceramic ink and subsequent calcination at 1500 ºC. Several key factors
2
O
3
[
2
O
3
support the design of the catalytic materials. The resulting 3D homogeneous network of
interconnected pores with well-defined morphology imparts a high catalytically active surface
area [82,83]. The woodpile design provides optimal adaptation to the dimensions of the
microwave reactors in which the transformations take place.
The cylindrical woodpile structure with a lattice of orthogonally interconnected rods is
showed in Fig. 1. The top view of the sintered structure is shown in Fig. 1b, where the surface
morphology exhibits a regular appearance of the rods without cracks, defects or
imperfections. To ensure the preparation of a reusable and highly active Al
2
3
O structure with
sufficient mechanical strength to withstand continuous contact with the reactor, the structure
was heated at 1500 °C for 2.5 h in air. This thermal treatment has a triple purpose: (i) to
remove the solvents and polymers employed during ink preparation, (ii) sintering of the
material to consolidate the structure and mechanical strength, and (iii) to increase the catalytic
activity of the material by increasing its Lewis acid character (by reducing the hydroxyl
groups present in the alumina structure) [59-72]. The weight of the sintered Al
structures obtained usually range from 0.330 - 0.370 g (0.350 g average). The cross-section of
the cylindrical Al structure observed in the scanning electron microscopy (SEM) image
Fig. 1c) demonstrates the internal uniformity of the structure after sintering. As seen in the
2
3
O woodpile
2
O
3
(
cross-section view, the layers are interconnected with a tetragonal symmetry that provides a
high surface-to volume ratio over a large area. A magnified view of the surface filament (Fig.
1
d) shows the dense assembly of Al
2
3
O crystals after sintering of the structure. As part of the
10

structural characterization of the novel catalytic material we performed XRD measurements
on the Al woodpile structure. Analysis of the XRD pattern obtained (Fig. 2) unequivocally
confirms the presence of well-defined peaks corresponding to the single phase of -Al
2
O
3
2
O
3
(JCPDS 75–1864).
It should be noticed that structural analysis (SEM and XRD) of one a representative
woodpile structure employed in 10 synthetic experiments unequivocally confirmed the
Al
2
O
3
identical morphology and composition to the observed for the woodpile structure before use.
Once the Al
2
3
O catalytic device had been synthesised and characterized, we focused
on the evaluation of its catalytic performance in Biginelli and Hantzsch reactions. These
multicomponent reactions enable the rapid and efficient assembly of diversely substituted 3,4-
dihydropyrimidin-2(1H)-ones and 1,4-dihydropyridines. It should emphasized that, in
addition to their excellent atom and bond economies, both transformations produce water as
the only side product [23-25], thus displaying optimal environmental factor metrics (E) [20-
2
2]. As these transformations are widely employed within the pharmaceutical industry to
prepare diverse active pharmaceutical ingredients (see Scheme 1 for selected examples)
10,11], the development of novel recyclable catalytic systems to achieve environmentally
[
friendly processes is very attractive.
The effectiveness of the 3D printed woodpile alumina structure to catalyse Biginelli
and Hantzsch reactions was first addressed by employing benzaldehyde (1a), ethyl
acetoacetate (2a) and either urea (3a) or ammonium acetate (5) as model reactants (Scheme
2
). Inspired by several references that describe successful Biginelli and Hantzsch reactions in
the absence of solvents [5,26-28], and with the aim of avoiding the use of unnecessary
reagents/solvents [20-22] while simultaneously preserving the integrity of the catalytic
system, we decided to perform the optimization studies under solvent free conditions. All
experiments were performed on a 2 mmol scale in sealed vials, employing a 3D printed
11

woodpile alumina structure of 0.350 g and microwave irradiation as the energy source.
Optimization experiments included variation of the temperature (60–120 ºC), the reaction
time (5–60 min) and the equivalents of the nitrogen source (1.2–3 equiv). The reported yields
(Table 1) are the mean of at least two experiments. A summary of the results obtained during
the preliminary exploration of the engineered 3D printed alumina catalyst for the substrates
tested is given in Scheme 2 and Table 1 (column 4). It can be seen that the alumina woodpile
structure provided highly effective catalytic activity in both heterocyclization reactions with
short reaction times. The optimal experimental conditions varied slightly for the Biginelli (90
ºC, 10 min) and Hantzsch (120 ºC, 30 min) reactions. A slight excess of the nitrogen source
was required for optimal yields (1.2 equivalents of urea for the Biginelli reaction and 2.5
equivalents of ammonium acetate for the Hantzsch reaction). In both cases the
transformations provided excellent yields of the model substrates [ethyl 6-methyl-2-oxo-4-
phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate (4a) and diethyl 2,6-dimethyl-4-phenyl-
1
,4-dihydropyridine-3,5-dicarboxylate (7a)]. It should be noted that under the optimized
conditions the target compounds solidified on cooling, thus facilitating their isolation by
washing with cold water and filtration and avoiding the use of solvents for compound
extraction.
Once the feasibility of the proposed method had been validated, it was decided to
explore the real role of the 3D printed alumina catalyst in these transformations. With this aim
in mind, we comparatively evaluated the reaction outcome (yield and reaction time) of model
Biginelli and Hantzsch reactions (compounds 4a and 7a) by comparing the results obtained
with the engineered woodpile catalyst (Table 1, column 4), with new experiments employing
either an equivalent amount in mass (0.350 g) of the alumina in powder form employed to
prepare the catalytic device (Table 1, column 5) or in the absence of any catalyst (Table 1,
column 6). The results obtained in these assays are shown in Table 1.
12

The comparative analysis of the yields obtained during these experiments highlighted
the remarkable efficacy of the 3D printed alumina catalyst reported here, which provided
yields that were substantially higher with respect to analogous experiments in which
powdered alumina was used (e.g., 15–23%) or under catalyst-free conditions (e.g., 20–35%).
Moreover, the data emphasise that the use of the 3D printed alumina catalyst ensures
complete consumption of the reactants in remarkably short reaction times (typically 5–25
min). It should also be noted that prolonged reaction times (up to 2 h) were required for
complete consumption of the precursors in the uncatalysed reaction and this favours the
appearance of side products. The determination of the specific surface area of the alumina
catalysts employed to perform the experiments documented in Table 1 provided unequivocal
evidences supporting the superior catalytic performance of the 3D printed structure. The BET
experiments highlighted the significant differences between the specific surface areas of both
2
2
samples (6.98 m /g for powdered alumina vs. 0.14 m /g for the 3D printed woodpile Al
2
O
3
structure). Although at a first glance the lower catalytic performance observed for the
powdered alumina, which has a higher specific area, could seem incongruous, this behaviour
could be a consequence of its inferior catalytic efficacy (since it was not thermally activated).
At the light of this data, the superior yields and reaction times observed when using the 3D
printed Al
2
3
O structure can be considerate even more remarkable, as the new material herein
described exhibits a 50-fold minor specific surface area, respect its powdered congener.
Several experiments employing two 3D printed alumina catalysts of different
dimensions [e.g., cylindrical woodpile structures with different height and diameter (7 mm - 7
mm and 14 mm - 7 mm) and weight (0.350 g and 0.600 g)] preliminarily validated the
potential scalability of the of the transformations and suggest the evaluated parameters did not
appear to be particularly critical for the reaction outcome. The 3D printed alumina catalyst
also provides advantages from practical point of view, by simplifying the experimental
13

protocols for the synthesis and isolation stages. Thus, the catalytic material can be easily
removed from the reactor with a laboratory tweezers, thus facilitating the implementation of
parallel-automated synthetic protocols.
In addition to catalytic efficacy, recyclability is a crucial issue to be considered during
the development of novel environmentally friendly heterogeneous catalytic systems.
Accordingly, the recyclability of the 3D printed alumina catalytic woodpile structure was
examined in representative examples of Biginelli and Hantzsch reactions (synthesis of 4a and
7
a). The average yields obtained during ten replicate experiments for the synthesis of
compounds 4a (1: 95%, 2: 95%, 3: 95%, 4: 95%, 5: 94%, 6: 94%, 7: 95%, 8: 94% and 9:
9
9
4%, 10: 94%) and 7a (1: 91%, 2: 91%, 3: 90%, 4: 91%, 5: 90%, 6: 90%, 7: 89%, 8: 90% and
: 89%, 10: 89%) confirmed that, after washing and drying under vacuum, the 3D printed
catalytic systems recovered from a reaction can be reused at least ten times in new reactions
without significant yield loss. Interestingly, these reactions also generated products with
purities similar to those obtained in the first run. The efficacy prompted us to carry out a
preliminary exploration of the scalability of the methodology described here. It was gratifying
to verify that replicates of the model reactions with 20 or 30 mmols of the starting materials
performed in a similar manner.
It should be highlighted that even though both heterocyclization reactions produce
water as a side product, the woodpile structure retained its excellent catalytic performance
after more than ten experiments (see above data). It has been shown that the surface properties
of oxides (including wettability) are mainly determined by the density of the hydroxyl groups
present on the surface [59-72]. Accordingly, our findings are consistent with those of previous
reports [59,84] and demonstrate that exposure of activated alumina to lipophilic environments
(e.g., that provided by the reactants tested here) retards rehydration of the material. The
excellent catalytic efficacy and recyclability of the material was accompanied by outstanding
14

mechanical stability. The woodpile structure did not show any signs of deterioration after
successive use in at least 10 replicates under either orbital or mechanical stirring.
Having established the feasibility of the proposed method, and having identified a set
of optimal experimental conditions to perform the Biginelli and Hantzsch reactions with the
obtained catalysts, the robustness and scope of the developed methodology was briefly
assessed by employing a set of assorted reactive precursors (Schemes 3 and 4). As part of this
study we included some relevant bioactive compounds and active pharmaceutical ingredients
(APIs) derived from the targeted chemotypes. We first focused on the synthesis of 3,4-
dihydropyrimidin-2(1H)-ones 4 (Scheme 3) employing a set of assorted aldehydes (1a−f), β-
dicarbonyl compounds (2a−d) and (thio)urea derivatives (3a−c). It was verified that the
previously optimized experimental conditions enable the rapid and efficient assembly of
assorted 3,4-dihydropyrimidin-2(1H)-ones (4a−h) bearing different substituents at positions 1
(H, Me), 2 (O/S), 4 (Aryl or heteroaryl) and 5 (ester or ketone). Once the reaction had
finished (as established by TLC) the target 3,4-dihydropyrimidin-2(1H)-one generally
solidified on cooling or was isolated by precipitation on crushed ice followed by conventional
filtration to give yields in the range 84–96% (Scheme 3). The purity of the crude isolated
adducts was generally greater than 95%, as judged by LC-MS analysis. The complete
analytical and spectroscopic data for all compounds described are included in the
experimental part. The robustness of this efficient and environmentally friendly protocol was
also validated by the synthesis of several bioactive 3,4-dihydropyrimidin-2(1H)-ones (4e–4h).
For this purpose we selected the antiviral agent Nitractin (4e) [10], the antimitotic drug
Monastrol (4f) [10] and the selective A2B antagonists SYAF-030 and ISAM-140 (4g and 4h)
[
31,32]. As documented in Scheme 3, excellent yields were obtained irrespective of the
substitution pattern present at the heterocyclic core or the complexity of the assembled
scaffold (e.g., monocyclic or tricyclic).
15

Driven by the excellent results obtained during the synthesis of the model
dihydropyridine 7a, and in order to challenge the scope of the 3D printed alumina catalyst, it
was decided to evaluate the feasibility of the two most frequent modifications of the Hantzsch
1
,4-dihydropyridine synthesis (Scheme 4) [23]. The first approach employed an aldehyde (1),
a β-dicarbonyl compound (2) and ammonium acetate and this provided symmetrically
substituted 1,4-dihydropyridines (7a−e). The second method, which take place in a sequential
fashion, used an aldehyde (1), a β-dicarbonyl compound (2) and an enamine (6), thus
furnishing unsymmetrically substituted 1,4-dihydropyridines (7f−h). It should be noticed that
the direct three-component approach to asymmetrically substituted 1,4-dihydropyridines
(7f−h) produced the desired compounds in modest yields (55–70%) and variable amounts of
its symmetrical analogues (15–25%). As for the previous series, all experiments were
performed under solvent free conditions on a 2 mmol scale in sealed microwave vials starting
with the temperature and reaction time optimized for model compound 7a. These experiments
validated the general applicability and robustness of the previously optimised conditions (120
ºC, 30–60 min), thus affording the desired 1,4-dihydropyridines with yields in the range 78–
9
3% irrespective of the method. A representative selection of compounds obtained is depicted
in Scheme 4.
As can be seen (Scheme 4), the 3D printed alumina structure exhibited excellent
catalytic performance for the two versions of the Hantzsch reaction, thus enabling the rapid
and efficient assembly of both symmetrically (7a−e) or unsymmetrically (7f−7h) substituted
1
,4-dihydropyridines. The robustness and scope of the approach reported here was further
validated by synthesising some representative L-type calcium channel blockers, which are
APIs commonly employed in the treatment of hypertension [e.g. Nifedipine (7i), Nisoldipine
(7j), Nitrendipine (7k) and Felodipine (7l)] [3,7-9,23]. It was gratifying to verify that the
16

optimized conditions provided rapid and efficient access to these drugs with excellent yields
and short reaction times. It should be noticed the use of enamines (6) as starting materials
enabled to obtain the targeted structures with shorter reaction times and milder experimental
conditions. As observed during the synthesis of 3,4-dihydropyrimidin-2(1H)-ones (4), the
purity of the crude isolated 1,4-dihydropyridines (7) was generally greater than 90%, as
determined by LC-MS analysis.
4
. Conclusions
A catalytic methodology has been developed that enables the efficient, experimentally simple
and environmentally friendly high-throughput synthesis of 1,4-dihydropyridines and 3,4-
dihydropyrimidin-2(1H)-ones. The novel strategy is based on the use of a recyclable 3D
printed Al
2
3
O catalytic structure that has a high surface-to-volume ratio and controlled
porosity, which provides remarkable efficacy as a Lewis acid during Biginelli and Hantzsch
reactions. The optimized conditions provided a rapid assembly of diverse 1,4-
dihydropyridines and 3,4-dihydropyrimidin-2(1H)-ones, including some representative drugs
and pharmacologically active derivatives. Broad substrate scope and excellent yields, solvent-
free conditions and easy isolation procedures are key features of this methodology.
Acknowledgements
The authors acknowledge the support of the Galician Government under Grants Award No.
GPC2013/019, GPC2014/003 and EM2014/022.
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21

Fig. 1. (a) Structure of the constructed Al
2
3
O catalytic device, (b) Top view of the sintered
structure (optical image), (c) SEM images of the cross-sectional view, and (d) surface
filament view of the sintered structure. The inset shows the filament surface at higher
magnification (scale bar = 10 μm).
Fig. 2. XRD pattern of Al
2
3
O sintered at 1500 ºC (JCPDS 75–1864).
22

F
O N
OH
O
2
NO2
O
O
H
N
O
S
O
O
O
Cl
O
H
O
H
S
H
O
N
O
Ph
N
O
O
N
N
O
N
F
O
N
N
H
N
H
N
H
N
H
N
H
F
NO2
N
O
N
O
NO2
Cl
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
N
H
NH2
Ph
Ph
N
H
N
N
H
H
Scheme 1. Representative examples of drugs and biologically active derivatives of the 1,4-
dihydropyridine and 3,4-dihydropyrimidin-2(1H)-one scaffolds [10,11].
Scheme 2. Proof of concept for model reactions and optimized conditions.
Scheme 3. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones 4 employing a 3D printed alumina
catalyst.
23

Scheme 4. Synthesis of 1,4-dihydropyridines employing a 3D printed alumina catalyst.
24

Table 1. Optimization studies during the synthesis of 4a and 7a.
Yield (%)
Comp.
Temp
Reaction
Time (min)
3
D-Printed
Powder
No
Catalyst
48
(
ºC)
§
§
Al
2
O
3
Al
2
O
3
4
4
4
4
4
4
7
7
7
7
7
7
a
a
a
a
a
a
a
a
a
a
a
a
60
10
15
10
15
10
15
15
30
15
30
15
30
78
89
85
89
95
95
70
79
81
85
92
94
57
66
70
80
74
82
61
65
69
73
75
79
60
80
80
90
90
70
70
90
90
55
56
61
65
70
56
60
62
66
71
74
120
120
§
2 3
Comparative experiments were performed employing 0.350 g of Al O
25