Alginic acid: A highly efficient renewable and heterogeneous biopolymeric catalyst for one-pot synthesis of the Hantzsch 1,4-dihydropyridines

Article abstract of DOI:10.1039/c4ra11801d

Alginic acid, a naturally occurring polysaccharide, in its granular form and without any post-modification was found to be an efficient, environmentally benign, easily recoverable and low-cost catalyst for the clean and rapid synthesis of 1,4-dihydropiridine derivatives (DHPs) just based on its polysaccharide architecture. The Hantzsch pseudo-four-component reaction of ethyl or methyl acetoacetate, ammonium acetate and different aldehydes is catalyzed by alginic acid efficiently under mild conditions to afford the desired products in high to quantitative yields and clean reaction profiles. Avoiding the use of any transition metal, the use of a one-pot and multi-component procedure for the synthesis of DHPs, the reusability of the catalyst and operational simplicity are important features of this methodology.

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Alginic acid: a highly efficient renewable and heterogeneous bio-polymeric
catalyst for one-pot synthesis of the Hantzsch 1,4-dihydropyridines
Mohammad G. Dekamin,*a Siamand Ilkhanizadeh,a Zahra Latifidoost,a Hamed Daemi,b Zahra Karimi,a
and Mehdi Barikanib
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Alginic acid, a naturally occurring polysaccharide, in its granular form and without any post-modification
was found to be an efficient environmentally benign, easily recoverable and low-cost catalyst for the
clean and rapid synthesis of 1,4-dihydropiridine derivatives (DHPs) just based on its polysaccharide
architecture. The Hantzsch pseudo-four-component reaction of ethyl or methyl acetoacetate, ammonium
acetate and different aldehydes is catalyzed by alginic acid efficiently under mild conditions to afford
desired products in high to quantitative yields and clean reaction profiles. Avoiding the use of any
transition-metal, the use of a one-pot and multi-component procedure for the synthesis of DHPs,
reusability of the catalyst and operational simplicity are important features of this methodology.
10
15 Designing and application of new eco-friendly chemicals and 45 1).12 Therefore, it can activate the reaction components by not
processes have almost been mandatory to keep and increase
human health standards due to growing environmental pollution
arising from industrial activities and their intensive impact on
living systems as well as economic point of view.1 Therefore,
only Bronsted acid centers but also hydrogen bonding, as a
heterogeneous organocatalyst.13 The catalytic activity of alginic
acid can also be intensified by the hydrophilic/hygroscopic nature
of these polymers when organic reactions produce water as their
20 science and technology has shifted toward green processes 50 byproducts. It is noteworthy that alginic acid is capable of
nowadays.2 Consequently, developing chemical processes using
more environmentally acceptable catalysts, chemicals and atom
efficient procedures have been emerged as subjects of innovation
in green chemistry. For instance, the terrible impact of non-
25 biodegradable wastes is still an open challenge in either
developed or developing countries.3 In this regard, great efforts
have been performed to use different bio-based feedstocks such
as chitosan,4 chitin,5 starch,6 cellulose,7 gelatin,8 wool9 and
alginates10 as biopolymeric support in the transition metal-based
30 heterogeneous catalytic systems. However, complete replacement
of transition metal-based heterogeneous catalytic systems by the
metal-free biopolymeric analogues is of significant importance
because of both toxicity and difficulty in separation of metal
catalysts from the final products, especially in the pharmaceutical
35 industry.11
absorbing 200-300 times its own weight in water.4d,10,14 These
requirements are fully met in the multicomponent reaction
(MCR) for synthesis of the Hantzsch 1,4-dihydropyridines (1,4-
DHPs).
55
Fig. 1. Chemical structure of alginic acid (1).
The Hantzsch pseudo-four-component reaction is the oldest
and most general known method for the synthesis of 1,4-DHPs
and
their derivatives
which
are
medicinally and
Alginic acid, also called algin or alginate, is a naturally
occurring anionic polysaccharide distributed widely in the cell
walls of brown algae. It can also be produced by a microbial
fermentation using special bacteria including Azotobacter and
40 Pseudomonas. Alginic acid is an acidic form of alginate and has a
plenty of both exposed carboxylic acid and hydroxyl groups
inside its backbone. Alginic acid and its salts are linear
copolymer with homopolymeric blocks of (1→4)-linked α-L-
guluronic acid (G) and β-D-mannuronic acid (M) residues (Fig.
60 pharmacologically very important molecules. Indeed, commercial
drugs such as nifedipine, amlodipine, nicardipine and felodipine
constitute a major class of ligands for L-type Ca2+ channels
(LTCC) blockers that are widely used to treat conditions such as
hypertension and angina (Fig. 2).15 Therefore, the attempts to
65 modify the conditions of the Hantzsch reaction are still of
growing importance.
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45 after 4 h (entry 1). Interestingly, the yield of the desired product
5a was significantly improved in shorter reaction times when
catalytic amounts of 1 were added to the reaction mixture in
EtOH (entries 2-5). The model reaction was also studied in other
solvents such as 50% aqueous EtOH (v/v), H2O and EtOAc using
50 alginic acid (1) loading of 10 mol% (entries 6-8). The obtained
yield of the desired product 5a in H2O was significantly less than
compared to EtOH under similar catalyst loading and reflux
conditions (entries 3 and 6). This may be attributed to both lower
solubility of the reactants and rendering the established
55 equilibriums between the reactants and reaction intermediates or
desired product 5a to the left side in H2O compared to EtOH
(Scheme 4). Finally, the effect of temperature on the obtained
yield and required reaction time was also examined (entries 9,
10). The obtained results demonstrated higher yields in shorter
60 reaction times can be obtained in EtOH under reflux conditions.
Fig. 2. Selected examples of 1,4-dihydropyridines demonstrating
pharmacological activity.
Literature survey shows that several modified methods for
Hantzsch reaction have been reported using different catalysts
mostly consisting of Bronsted or Lewis acids in recent years.16
5
For example, homogeneous catalytic systems such as p-TSA,17a
17b
3,4,5-trifluorobenzeneboronic acid in ionic liquid or InCl3,
Cd(NO3)2.4H2O,17c Yb(OTf)3,17d Sc(OTf)3,17e hafnium (IV)
bis(perfluorooctanesulfonyl)imide complex [Hf(NPf2)4]17f and
10 Zn[(L)proline]2,17g can be mentioned. On the other hand, organic
18a
Lewis bases such as PPh3 and TMS-protected prolinol18b as
Table 1 Optimization of the Hantzsch pseudo-four-component reaction
for the synthesis of 5a catalyzed by alginic acid (1)a
well as bifunctional L-proline under ultrasound irradiation18c have
also been reported. Furthermore, enzymes such as candida
antarctica lipase B19a or baker’s yeast,19b ionic liquids,19c and
15 non-ionic surfactant Triton X-10019d demonstrated catalytic
activity for DHP synthesis. In spite of their merits, most of these
methods suffer from the use of hazardous or expensive catalysts
or solvents, long reaction times, high temperature and
complicated workup. Although some heterogeneous catalysts
65
20 such as sulfonic acid supported γ-Fe2O3 or cellulose,20b silica
20a
supported
heteropolyacids,20d
12-tungstophosphoric
Ce(SO4)2-SiO2,20e
acid,20c
preyssler
Entry Catalyst loading
(mol%)
Solvent
Temp.
(°C)
Time
(min)
4 h
Yieldb
(%)
46
self-assembled
tinphosphonate nanoparticles,20f Zn-VCO3 hydrotalcite,20g and
hydromagnesite20h have been introduced in the recent years but
25 there is still room to improve the reaction conditions in terms of
the use of renewable biopolymeric and transition metal-free
heterogeneous catalysts under mild conditions. In continuation of
our interest to explore application of biopolymers in different
fields, especially their catalytic activity without any post-
30 modification as well as MCRs,4d,21 we wish herein to report the
first catalytic activity of alginic acid (1) as a mild, highly
1
2
3
4
5
6
-
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
20
15
10
5
40
98
40
98
50
96
2 h
63
10
10
3 h
65
Aqueous
EtOHc
EtOAc
EtOH
EtOH
EtOH
2 h
77
7
8
9
10
10
10
10
Reflux
25
5 h
3.5 h
2 h
62
89
92
92
effective
and
convenient
bifunctional
heterogeneous
10
11d
50
biopolymeric catalyst for the one-pot synthesis of 1,4-
Reflux
60
dihydropyridines via Hantzsch reaction in EtOH (Scheme 1).
a
70
Reaction conditions: 4-Chlorobenzaldehyde (2a,
1
acetoacetate (3a, 2 mmol), ammonium acetate (4a, 1.2 mmol). Isolated
mmol), ethyl
b
c
d
yields.
(50% v/v).
The scale up of model reaction using 4-
chlorobenzaldehyde (2a,10 mmol), ethyl acetoacetate (3a, 20 mmol), and
ammonium acetate (4a, 11 mmol).
75
Furthermore, the catalytic activity of the alginic acid (1) was
35
examined in the next step to prove its feasibility as
a
Scheme 1. Pseudo-four-component reaction of different aldehydes 2, β-
ketoesters 3, and nitrogen sources 4 catalysed by alginic acid (1) in EtOH
under reflux conditions.
heterogeneous biopolymeric catalyst for scale up of the Hantzsch
80 reaction (entry 11). Interestingly, the alginic acid was found to be
an efficient catalyst for performing of the Hantzsch reaction at
higher scales. Therefore, alginic acid (1) loading of 10 mol%
(17.6 mg per 1 mmol of aldehyde 2) in EtOH under reflux
conditions, as the optimized reaction conditions, was developed
85 to other derivatives of aromatic and α,β-unsaturated carbonyl
compounds (2b–p) and amines (4a–c) for the synthesis of the
desired 1,4-DHPs 5 (Fig. 3 and Scheme 2).
To evaluate the catalytic activity of alginic acid (1) for the
40 synthesis of 1,4-DHPs, first the reaction of 4-chlorobenzaldehyde
(2a), ethyl acetoacetate (3a), and ammonium acetate (4a) (2:1:1.2
mole ratio) was investigated as the model reaction in EtOH. The
results are summarized in Table 1. In the absence of any catalyst,
only a poor yield of the corresponding 1,4-DHP 5a was obtained
2
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Fig. 3. Different aldehydes (2a-p) and ammonia derivatives (4a-c)
examined in the Hantzsch MCR catalysed by alginic acid (1).
To our delight, the diludine (5b), a substance with noteworthy
pharmaceutical and food applications as well as organic reductive
agent,15,22 was prepared in short reaction time and excellent yield
(See also ESI). Moreover, all the aromatic aldehydes having
either electron-withdrawing substitutes (2c-2h) or electron-
donating ones (2j-2o) reacted smoothly to provide the
5
10 corresponding Hantzsch esters (5c-5o) in good to excellent
isolated yields. However, the aldehydes carrying nitro groups
(2d, 2e) afforded lower yields compared to those having other
electron-withdrawing substituents rather than nitro group or even
electron-donating ones. Lower yields obtained for aldehydes
15 having meta- and para-nitro substituents (2d, 2e) may be
attributed to the competitive formation of less reactive
corresponding imines.23 The obtained yields in these cases were
improved somewhat by late addition of aldehydes 2d or 2e to the
reaction mixture (89% and 84%, respectively). On there hand, the
20 effect of nitrogen source in the Hantzsch reaction catalysed by
alginic acid (1) was also examined. It has been reported that
ammonium salts of carbonate or bicarbonate show somewhat
higher efficiency than the acetate salt in hot water.24 However, it
should be noted that those former salts produce CO2 on their
25 decomposition as reaction proceeds (Scheme 4). The greenhouse
effect of CO2 is well known. Therefore, ammonium acetate is one
of the best choice as ammonia source in the Hantzsch reaction.
Furthermore, aliphatic or aromatic amines including benzyl
amine (4b) and p-toluidine (4c) were also examined. Lower
30 yields of the desired DHPs (5q and 5r, respectively) can be
attributed to the more steric hindrance and stronger resonance
effect of these amines compared to ammonium acetate.25
Scheme 2. Pseudo-four-component synthesis of different diethyl 1,4-
DHP-3,5-dicarboxylate (5a-r) catalysed by alginic acid (1) in EtOH under
reflux conditions.
40
In the next stage, the size effect of the alkyl group of ester
moiety in the β-ketoester 3 on the yield of the expected 1,4-DHPs
was also investigated using methyl acetoacetate (3b) instead of
ethyl acetoacetate (3a). Corresponding 1,4-DHPs 6a-p were
obtained in good to excellent yields (Scheme 3, See also ESI). In
35
45 all of studied cases, similar trend of reactivity were observed
compared to ethyl acetoacetate (3a).
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proposed for the synthesis of 1,4-DHPs 5-6 through MCR of
aldehydes 2, β-ketoesters 3, and nitrogen sources 4 catalysed by
10 alginic acid (1) (Scheme 4). First, alginic acid (1) activates the
carbonyl functional group of aldehyde 2 for the next addition of
enol form of β-ketoesters 3 on it to form the corresponding
Kenovenagle intermediate (II). This intermediate is also
protonated by alginic acid (1) to be activated for the next Michael
15 addition of enol form of β-ketoesters 3. Then, one of the keto
functional groups in the intermeadiate (IV) is activated through
proton transfer from alginic acid (1) to react with the nitrogen
source 4 and give imine intermediate (V). This later intermediate
is also activitaed through proton transfer from alginic acid (1) to
20 facilitate its subsequent tautomerision to the corresponding
enamine (VI). In the next step, alginic acid (1) activates the
remaining keto functional group for ring closure by amino group
of the enamine moiety. Finally, elimination of third H2O
molecule is catalysed by alginic acid (1) to afford the desired 1,4-
25 DHP 5-6. Furthermore, all the above steps can be competitively
catalysed through hydrogen bonding rather than proton transfer
with weaker interactions. On the other hand, ring closure may
take place from position 4- of 1,4-DHP rather than its 1-position,
alternatively. This means that enamine formation and
30 condensation with the second molecule of β-ketoesters 3 can take
place prior to Micaheal addition in the above proposed
mechanism.
F
Cl
O
O
O
O
O
O
H
H
O
O
O
O
O
O
N
N
H
N
H
H
6c, 97%
6b, 94%
6a, 96%
Br
NO2
NO2
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
6d, 85%a
6d, 90%a
6e, 79%a
6e, 86%a
6f, 94%
Cl
Cl
O
Cl
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
On the other hand, the reusability of alginic acid (1) was also
35 investigated for at least 6 runs. The results are summarised in Fig.
4. The obtained results demonstrated that alginic acid (1) is
reusable for the practical applications in the Hantzsch 1,4-DHPs
synthesis.
6g, 88%
6h, 93%
6i, 95%
CH3
OMe
OH
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
6j, 93%
6k, 92%
6l, 90%
OH
OMe
O
S
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
6m, 91%
6n, 92%
6o, 97%
40
Fig. 4. Reusability of alginic acid catalyst (1) for the Hantzsch MCR to
afford 5a.
O
O
In conclusion, a new, renewable and readily recoverable
biopolymeric catalyst for the MCR Hantzsch reaction has been
45 described which displays particularly high efficiency just based
on polysaccharide architecture of alginic acid. Avoiding the use
of any transition-metal, clean reaction profiles, the use of a one-
pot and multi-component procedure for the synthesis of DHPs,
reusability of the catalyst and operational simplicity are the
50 important features of this methodology. Further developemet of
this methodology to bicyclic and tricyclyclic derivatives of DHPs
are currently underway and will be presented in due course.
O
O
N
H
6p, 93%
a One step, one-pot reaction
b Two step, one-pot reaction
Scheme 3. Pseudo-four-component synthesis of different dimethyl 1,4-
DHP-3,5-dicarboxylate (6a-p) catalysed by alginic acid (1) in EtOH
under reflux conditions.
5
According to obtained results, the following mechanism can be
4
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Scheme 4. Plausible mechanism for the Hantzsch pseudo-four-component reaction of different aldehydes 2, β-ketoesters 3, and nitrogen sources 4
catalysed by alginic acid (1).
5
‡ This research was supported by The Research Council of Iran
University of Science and Technology (IUST), Tehran, Iran (grant no.
Notes and references
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DOI: 10.1039/C4RA11801D
Graphical Abstract
Alginic acid:
a
highly efficient renewable and
5
heterogeneous bio-polymeric catalyst for one-pot
synthesis of the Hantzsch 1,4-dihydropyridines
Mohammad G. Dekamin, Siamand Ilkhanizadeh, Zahra
Latifidoost, Hamed Daemi, Zahra Karimi and Mehdi Barikani
10
15
Alginic acid was found to be an efficient, environmentally benign, easily
recoverable and low-cost catalyst for clean synthesis of 1,4-
dihydropiridine derivatives (DHPs).
20
25