One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

Article abstract of DOI:10.3762/BJOC.16.235

A rapid route for obtaining unsymmetrical 1,2-dihydropyridines (1,2-DHPs) as opposed to 1,4-dihydropyridines (1,4-DHPs) has been achieved via a one-pot multicomponent Hantzsch reaction. A benign protocol has been developed for the preparation of various 1

Full text of DOI:10.3762/BJOC.16.235

One-pot multicomponent green Hantzsch synthesis of
1,2-dihydropyridine derivatives with antiproliferative activity
Giovanna Bosica*1, Kaylie Demanuele1, José M. Padrón2 and Adrián Puerta2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 2862–2869.
1Department of Chemistry, University of Malta, Msida, MSD 2080
Malta and 2BioLab, Instituto Universitario de Bio-Orgánica “Antonio
González” (IUBO-AG), Universidad de La Laguna, c/Astrofísico
Francisco Sánchez 2, 38206 La Laguna, Spain
https://doi.org/10.3762/bjoc.16.235
Received: 29 August 2020
Accepted: 06 November 2020
Published: 24 November 2020
Email:
Giovanna Bosica* - giovanna.bosica@um.edu.mt
This article is part of the thematic issue "Green chemistry II". The article is
dedicated to the memory of Prof. Bosica`s mother, Mrs. Maria Nespoli.
* Corresponding author
Associate Editor: L. Vaccaro
Keywords:
antiproliferative activity; 1,2-dihydropyridines; green Hantzsch
synthesis; heterogeneous catalysis; one-pot multicomponent reaction
© 2020 Bosica et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A rapid route for obtaining unsymmetrical 1,2-dihydropyridines (1,2-DHPs) as opposed to 1,4-dihydropyridines (1,4-DHPs) has
been achieved via a one-pot multicomponent Hantzsch reaction. A benign protocol has been developed for the preparation of
various 1,2-dihydropyridine derivatives using heterogenized phosphotungstic acid on alumina support (40 wt %). High yields of
over 75% have been accomplished in just 2–3.5 h after screening several heterogeneous catalysts and investigating the optimal
reaction conditions. The catalyst chosen has passed the heterogeneity test and was shown to have the potential of being reused for
up to 8 consecutive cycles before having a significant loss in activity. In addition, aromatic aldehydes gave the aforementioned
regioisomer while the classical 1,4-DHPs were obtained when carrying out the reaction using aliphatic aldehydes. The preliminary
study of the antiproliferative activity against human solid tumor cells demonstrated that 1,2-DHPs could inhibit cancer cell growth
in the low micromolar range.
Introduction
A multicomponent approach towards the synthesis of the (1921), and Ugi (1959) reactions [3]. The significance of such a
desired product offers a number of advantages over a stepwise phenomenal approach for the synthesis of novel compounds
method. Such advantages include the development of a design first began as a way of increasing the chemical libraries and
that is: cheaper, simpler, economical, and environmentally then shifted to obtaining products that are in high demand on an
friendly [1,2]. Multicomponent reactions are not new to industrial scale at a cheaper and more benign way [4]. Recently,
research. The pioneer multicomponent reactions are the negative human impacts have been greatly witnessed as a result
Hantzsch (1882), Biginelli (1891), Mannich (1912), Passerini of population growth, so environmentally friendly design has
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become one of the most important contributions. As a result, ry amines, and urea. The oxidation of dihydropyridines to
such research has grown exponentially in the past decade [5,6]. pyridines has been achieved using mild oxidizing agents
[7,17,18].
The work conducted by the German chemist Arthur Hantzsch
exploded in the synthetic interest in dihydropyridines and One of the greatest limitations of this synthesis is however the
pyridines when the pharmacological usefulness of these com- fact that the dihydropyridines that are obtained are usually the
pounds in medicine was discovered [7]. The structural resem- 1,4-symmetrical ones. This multicomponent reaction has been
blance of these compounds to the coenzyme reduced nicotin- thought to have one of the most complex mechanisms since
amide adenine dinucleotide (NADH) sparked the potential phar- various routes might take place, and the mechanism depends
maceutical properties, and till today, the Hantzsch synthesis is much on the identity of the substrates and the reaction condi-
the main route for obtaining such products, which are eventu- tions used [18]. Cao and collaborators have managed to synthe-
ally used as active pharmaceutical ingredients in the pharma- size the 1,2-dihydropyridine (1,2-DHP) regioisomer as the main
ceutical industry [3,8]. An analysis of the market shows that product through the Hantzsch synthesis at room temperature
there are over 7000 drugs derived from dihydropyridines, some and solvent-free conditions, irrespective of the electronic effect
of which are blockbuster drugs, such as Tamiflu®, dioscorine, of the substituted benzaldehydes studied [19]. This was a
ibogaine, and isoquinuclidines [9,10].
further improvement of the reaction since the usual regioisomer
has always been reported to be the 1,4-DHP. Cao et al. have
Classically the Hantzsch synthesis involved the condensation of suggested an alternative mechanism for this route. When the
2 equivalents of the β-ketoester ethyl acetoacetate (2) with same reaction was conducted under argon, they obtained a mix-
benzaldehyde (1a) and ammonia (Scheme 1) [11]. This proce- ture of the two regioisomers (1,4-DHP/1,2-DHP 32:68), proving
dure was later optimized over the years using different sub- further the complexity of this reaction [19].
strates by varying the β-ketoesters and aldehydes in order to
prepare a larger array of 1,4-dihydropyridines (1,4-DHPs) [12]. Therefore, continuing our studies for the development and ap-
In addition, further developments were made to the methodolo- plication of environmentally friendly methodologies for multi-
gy in order to enhance the reaction yield and also to reduce the component reactions [20], we attempted to find a green catalyst
reaction time. Other recent developments involve reducing the that could provide a wide substrate scope for the Hantzsch syn-
energy and waste that is produced in the reaction for a more en- thesis of 1,2-dihydropyridines in a short reaction time.
vironmentally friendly synthesis [13-16]. The source of nitrogen
has also been varied from the classical use of ammonia. The In order to achieve a green method, apart from utilizing a multi-
most common nitrogen source reported in literature is ammoni- component reaction as a route providing a high atom economy,
um acetate (3). Others include the use of oxahydrazines, prima- heterogeneous catalysis should be used since it offers a greener
Scheme 1: The classical Hantzsch synthesis between benzaldehyde (1a), ethyl acetoacetate (2), and ammonium acetate (3) as well as the synthesis
highlighted in this work.
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alternative to homogeneous catalysis and ideally a solvent-free (Table 1, entry 9), a 30 wt % PW loading on montmorillonite
design to reduce the amount of solvent waste [21,22]. These K30 clay (Table 1, entry 11), and a 40 wt % PW loading on
two factors will reduce the amount of hazardous chemicals by alumina (Table 1, entry 12).
reducing the amount of solvent in the reactor and during the
workup of the product. A solid insoluble catalyst can easily be The study on the optimal reaction conditions shed a light on the
removed from the reaction mixture via filtration, unlike a acidity and the physical characteristics required for the reaction
soluble one [23-25].
to be successful; the reaction requires strong acids. In addition,
a peculiar result was obtained when analyzing the structure of
the product obtained since the less frequently reported regio-
Results and Discussion
According to literature, the reaction has shown to work best and isomer, the unsymmetrical 1,2-DHP, was being obtained in a
most efficiently under acidic conditions since such conditions high yield and with a high selectivity. At this stage, further opti-
enhance the selectivity. When the model reaction between mization and reaction trials were required in order to better
benzaldehyde (1a), ethyl acetoacetate (2), and ammonium understand the reaction conditions needed for the best results in
acetate (3, Scheme 1) was carried out in the absence of any terms of yield and selectivity of this transformation. The
catalyst, it turned out to be very slow and, according to GC following investigation on each selected catalyst included
chromatograms, stopped in the early stages since the peaks of changes in the molar ratio of the reagents, in the amount of
the corresponding starting materials of the model reaction catalyst, and in the temperature as well as the effect of the
appeared. A number of acidic catalysts was then analyzed chosen green solvents (Figure 1).
before choosing the optimal catalyst (Table 1). The most signif-
icant result selected was based on the yield and reaction time.
Increasing the temperature did not significantly change the reac-
tion yield or reduce the reaction time, while the presence of a
The Nafion® catalysts showed the most promising results when green solvent, such as water or ethanol, negatively impacted the
carrying out the screenings. These catalysts were not further course of the reaction. Increasing the amount of catalyst did
studied since they are no longer commercially available, and the have a positive effect on the reaction, however, this was ob-
preparation requires rather extreme conditions. The four cata- served only up to a certain weight. The molar ratio of the
lysts chosen for further investigation according to the prelimi- reagents was altered by increasing the amount of ammonium
nary screenings shown in Table 1 were the activated resin acetate (3) in the model reaction. This again had no particularly
Amberlyst® 15 (Table 1, entry 6), 40 wt % PW on silica positive effect. Since the presence of water was shown to be
Table 1: Screening of acidic heterogeneous catalysts.
entrya
catalyst
yield (%)b
reaction time (h)
1
Nafion® NR-50
88
96
72
48
68
82
49
37
61
40
83
94
85
80
74
43
5
2
Nafion® SAC-13
5
3
montmorillonite K30
4.5
5.5
5.5
5
4
Dowex® 50W
5
Amberlyst® 15
6c
7
activated Amberlyst® 15
40 wt % silicotungtstic acid on cellulose
40 wt % silicotungstic acid/Al2O3
40 wt % phosphotungstic acid (PW)/SiO2
20 wt % silicotungstic acid/montmorillonite K10
30 wt % PW/montmorillonite K30
40 wt % PW/Al2O3
6
8
6
9
6
10
11d
12
13
14
15
16
6
2.5
3.5
4
40 wt % PW/acidic Al2O3
30 wt % PW/Amberlyst® 15
50 wt % H3PO4/Al2O3
4.5
5
30 wt % phosphomolybdic acid/Amberlyst® 15
6
aReaction carried out under neat conditions using 0.04 g/mmol of the catalyst and a 1a/2/3 1:2:1 ratio. bYield of the pure isolated product. cActivation
by heating overnight at 100 °C. d1a/2/3 1:2:2 ratio.
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detrimental, the ammonium acetate (3) used was left to dry in a
desiccator before use.
Reaction monitoring was mostly done using thin-layer chroma-
tography (TLC) and at times also GC. These techniques showed
the occurrence of at least three intermediates before reaching
the ultimate product. No side products were observed at the end
of all reactions, which shed a light on the selectivity obtained
using the developed protocol. The results from the optimization
trials are highlighted in Figure 1.
The optimal reaction conditions chosen included room tempera-
ture, a stoichiometric molar ratio of the reactants, using 40 wt %
PW loaded on alumina under solvent-free conditions. These
conditions satisfied the green protocol we were aiming for.
Therefore, from this stage we moved onto the next one by
changing the substrates to explore the versatility of the de-
veloped method.
The selectivity was promising even for the other substrates used
(Table 2). Various substituted benzaldehydes were used, and all
gave similar results. Deviations from the model reaction
occurred in terms of the expected reaction time and yield, but
generally, the deviations from the model reaction were minimal.
Unexpectedly, when carrying out the reaction using aliphatic
aldehydes under the same conditions, a different regioisomer,
the commonly reported 1,4-DHP instead of the 1,2-DHP, was
Figure 1: Optimization trials with the selected solid catalysts.
Table 2: Screening of different substrates.
producta
R
yield of 5 (%)b
time (h)
5a
5b
5c
5d
5e
5f
C6H5 (1a)
94
73
96
65
62
62
64
92
90
81
4.5
3.5
4
2-OH-C6H4 (1b)
2,4-(OH)2-C6H3 (1c)
2,4-Cl2-C6H3 (1d)
3-CH3O-C6H4 (1e)
2-CH3O-C6H4 (1f)
4-CH3-C6H4 (1g)
4-N(CH3)2-C6H4 (1h)
naphthyl (1i)
6
5
5.5
4.5
4
5g
5h
5i
4
5j
2,3-(methylenedioxy)-C6H3 (1j)
4.5
aThe reactions were performed on a 5 mmol scale under neat conditions at room temperature and in the presence of 0.04 g/mmol 40 wt % PW on
alumina at a molar ratio of 1:2:1. bPure isolated product.
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produced in the form of 4 with a high selectivity (Table 3), Green metrics
which was also reported by Cao and collaborators [19].
The green character of a reaction can be approximately quanti-
fied by calculating both the E-factor and the atom economy
(AE), amongst other factors. The AE of the Hantzsch synthesis
Catalyst characterization and recyclability
The catalyst was analyzed by X-ray fluorescence (XRF) spec- for the model reaction involving benzaldehyde (1a, 1 mol),
troscopy in order to ascertain the PW/Al2O3-support ratio. The ethyl acetoacetate (2, 2 mol) and ammonium acetate (3, 1 mol)
mass percentage ratio of tungsten, which is the main compo- is equal to 74%:
nent of the catalyst, and aluminium, the major element of the
support, was used to determine the percentage of PW in the en-
semble. According to the data obtained by XRF spectroscopy,
(1)
the PW loading of 38.4 wt % was concordant to the theoretical
value of 40 wt %.
When the reusability test was carried out with the model reac-
tion using the optimal catalyst, 40 wt % PW on alumina, a sub- In order to take the amount of waste generated by the materials
stantial yield loss of 13% was observed after the 8th cycle while that are not directly involved in the reaction into consideration,
the required reaction time increased by 30 minutes after the 7th the E-factor was also calculated:
cycle (Figure 2). This result confirmed the green character of
the protocol, which is what we were aiming for.
(2)
The mass used for the calculation is that of the starting materi-
als of the model reaction and that of the catalyst used in the
general procedure.
Biological screening
The 1,4-DHP scaffold displays an extensive range of biological
activities, including reversing multidrug resistance (through the
inhibition of the P-glycoprotein) [26] and antiproliferative
effects on human cancer cell lines [27]. We wondered whether
the studied 1,2-DHPs could interfere with tumor cell growth.
Figure 2: Graphical representation of the results obtained in the reus-
ability test.
Thus, we selected a small subset of 1,2-DHPs and screened
them against a panel of six human solid tumor cell lines. The
Table 3: Results obtained when using the aliphatic aldehydes 1 in the Hantzsch synthesis.
producta
aldehyde
yield of 4 (%)b
time (h)
4b
4c
cyclohexanal (1k)
penten-2-al (1l)
82
79
4
4
aThe reactions were performed on a 5 mmol scale under neat conditions at room temperature and in the presence of 0.04 g/mmol 40 wt % PW on
alumina at a molar ratio of 1:2:1. bPure isolated product.
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Beilstein J. Org. Chem. 2020, 16, 2862–2869.
results are shown in Table 4. Interestingly, the majority of the point apparatus. Reactions were monitored by TLC and GC.
1,2-DHPs displayed antiproliferative activity against all cell Mass spectra were measured via a Thermo Scientific GC/MS
lines, in the low micromolar range. The most active compound DSQ II device, which contained a column: EC-5 30 m ×
was 5e, which exhibited GI50 values in the range of 0.25 mm i.d. × 0.25 µm or using the direct-infusion method
2.7–5.6 μM. The results obtained are comparable to those of the using a Waters® ACQUITY® TQD system with a tandem
standard anticancer drug cisplatin (CDDP), which was used as quadrupole mass spectrometer. The software used was Ther-
reference drug.
moXcalibur 2.2 SP1.48. The XRF spectroscopy analysis of the
catalyst was performed using a Bruker S2 Ranger®.
Conclusion
The one-pot multicomponent Hantzsch reaction for the synthe- Catalyst preparation
sis of substituted dihydropyridines was performed under green The method previously reported by Zhu et al. was used to
heterogeneous and neat conditions in the presence of prepare several supported heteropoly acids (silicotungstic and
0.04 g/mmol of a 40 wt % phosphotungstic acid on alumina PW) on various supports at different loadings [28]. For 1 g of a
catalyst, which is simple, safe and environmentally benign to catalyst batch with a loading of 20 wt %, 0.8 g of the support
prepare, fully recoverable, and reusable for up to 8 runs. A high and 0.2 g of a heteropoly acid were stirred in a minimum
AE of 74% and a low E-factor of 0.72 highlight the green char- amount of distilled water to form a slurry for 8 hours at room
acter of the procedure. More importantly, PW/alumina was able temperature in a 10 mL round-bottomed flask. Then, the cata-
to catalyze a wide range of reactions involving different aromat- lyst was dried overnight at 110 °C and ultimately calcined at
ic aldehydes to give products in good to excellent yields and 250 °C in a furnace under air for 4 h to obtain a white powder
interestingly all with the same general structure, corresponding (1 g), which was stored in a calcium chloride/silica-filled desic-
to the 1,2-DHP regioisomer, unless when using aliphatic alde- cator.
hydes.
General method
The general method involved the addition of 1 equiv of the
Experimental
General
aldehyde (5 mmol), 2 equiv ethyl acetoacetate (2, 10 mmol),
All the chemicals used were purchased form Sigma-Aldrich. IR and 1 equiv ammonium acetate (3, 5 mmol) in one vessel. The
spectroscopy studies were conducted on a Shimadzu IRAf- reactants were left to stir together with 0.2 g of the catalyst
finity-1 FTIR spectrometer calibrated against 1602 cm−1 poly- (40 wt % PW on alumina). At intervals of 30 minutes, the reac-
styrene absorbance spectra. The 1H NMR and 13C NMR spec- tion mixture was analyzed using TLC, GC, or both. With time,
tra were measured on a Bruker Avance III HD® NMR spec- the reaction mixture was observed to change from colorless to
trometer equipped with an Ascend 500 11.75 Tesla supercon- yellow, which darkened or brightened to orange or yellow and
ducting magnet, operating at 500.13 MHz for 1H and thickened with the occurrence of crystals on the sides of the
125.76 MHz for 13C, and a multinuclear 5 mm PABBO probe. flask. Once the spot or the peak corresponding to the benzalde-
Melting points were recorded on a Stuart® SMP11 melting hyde disappeared on the TLC plate or in the gas chromatogram,
Table 4: Antiproliferative activity (GI50 values) of selected 1,2-DHPs against human solid tumor cells.a
compound
cell line
SW1573
A549
HBL-100
HeLa
T-47D
WiDr
5a
29 ± 4.6
>100
23 ± 1.8
>100
21 ± 2.0
28 ± 7.5
12 ± 4.5
2.7 ± 0.5
26 ± 4.0
22 ± 6.6
28 ± 4.6
18 ± 5.0
4.9 ± 1.0
1.8 ± 0.5
31 ± 0.7
>100
21 ± 2.5
>100
22 ± 2.4
>100
5b
5d
5e
14 ± 3.1
5.1 ± 0.3
43 ± 14
18 ± 4.9
34 ± 4.7
23 ± 6.8
16 ± 6.7
4.9 ± 0.2
19 ± 3.0
4.8 ± 0.4
42 ± 6.2
20 ± 0.9
38 ± 4.0
26 ± 2.0
16 ± 3.5
1.9 ± 0.2
22 ± 1.2
5.6 ± 1.0
49 ± 12
18 ± 6.8
33 ± 6.1
30 ± 0.3
11 ± 1.7
2.7 ± 0.4
17 ± 3.6
4.0 ± 0.3
33 ± 5.1
22 ± 2.1
31 ± 0.9
20 ± 2.0
15 ± 1.9
17 ± 3.3
17 ± 1.2
3.3 ± 0.5
41 ± 9.6
18 ± 1.6
39 ± 8.9
33 ± 4.8
19 ± 3.3
23 ± 4.3
5f
5g
5h
5i
5j
CDDP
aGI50 values are given in µM. The standard deviation was calculated from at least two independent experiments. CDDP (cisplatin) was used as a
reference compound. Values in bold face represent the best antiproliferative data against tumor cell lines (GI50 < 10 µM).
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Beilstein J. Org. Chem. 2020, 16, 2862–2869.
the time was taken as the reaction was finished. The reaction (MCIU/AEI/FEDER, UE). A. P. thanks the EU Social Fund
mixture, obtained as a viscous oil, was filtered through a sinter (FSE) and the Canary Islands ACIISI for a predoctoral grant
funnel to remove any catalyst and washed using acetone, which TESIS2020010055.
was then evaporated in a rotary evaporator. The resultant crys-
tals were then recrystallized using hot ethanol. The products
ORCID® iDs
were then characterized via IR, NMR, and MS analysis.
Giovanna Bosica - https://orcid.org/0000-0002-5674-870X
José M. Padrón - https://orcid.org/0000-0001-6268-6552
Adrián Puerta - https://orcid.org/0000-0002-7975-1960
Hot filtration test
The optimized model reaction was monitored by GC, and the
catalyst was left in the reaction mixture for 30 minutes in order
to confirm heterogeneity. During these 30 minutes, the reaction
started. However, upon removal of the catalyst by filtration, the
reaction was left to carry on but stopped, and therefore catalyst
leaching was not evident.
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