Al2(so4)3 is an efficient and mild acid catalyst for the one-pot, four-component synthesis of polyhydroquinoline

Article abstract of DOI:10.4067/S0717-97072014000100017

Aluminium sulfate has mild acidity, yet the acidity of aluminium sulfate is not taken advantage of in organic synthesis. Here, we utilized aluminium sulfate for the first time in a multicomponent reaction for the synthesis of polyhydroquinoline. A four-co

Full text of DOI:10.4067/S0717-97072014000100017

J. Chil. Chem. Soc., 59, Nº 1 (2014)
Al2(SO4)3 IS AN EFFICIENT AND MILD ACID CATALYST FOR THE ONE-POT, FOUR-COMPONENT
SYNTHESIS OF POLYHYDROQUINOLINE
PRAMOD KULKARNI*
Department of Chemistry, Hutatma Rajguru Mahavidyalaya, Rajgurunagar, Pune (MS) India 410505
(Received: May 22, 2013 - Accepted: January 12, 2014)
ABSTRACT
Aluminium sulfate has mild acidity, yet the acidity of aluminium sulfate is not taken advantage of in organic synthesis. Here, we utilized aluminium sulfate
for the first time in a multicomponent reaction for the synthesis of polyhydroquinoline. A four-component one-pot synthesis of polyhydroquinoline was carried out
by condensing dimedone, aromatic aldehyde, ethyl acetoacetate, and ammonium acetate using a catalytic amount of aluminium sulfate (10%) refluxed in ethanol.
The present protocol using aluminium sulfate a mild solid catalyst has several merits, such as low cost, high yield, and shorter reaction time, with no byproducts.
Keywords: Aluminium sulfate, Dimedone, Dihydropyridine, Ethyl acetoacetate Polyhydroquinoline, Four components.
Table 1 Catalytic activity of soild acid and Lewis acid in Hantzsch
reactiona
INTRODUCTION
Recently, increased efforts have been focused on the synthesis of 1,4–
dihydropyridine compounds due to their significant biological activity 1-5. For
example, dihydropyridine drugs such as nifedipine, nicardipine, amlodipine
and others are effective cardiovascular agents for the treatment of hypertension
6, 7. 4-Aryl-1,4-dihydropyridines have been explored for their calcium channel
activity and the heterocyclic rings are found in a variety of bioactive compounds
such as vasodilators, bronchodilators, and anti-atherosclerotic, anti-tumor,
anti-diabetic, geroprotective and heptaprotective agents 8-11. Moreover, these
Entry
Catalyst (20%mol)
Silicotungstanic acid
Stannous chloride
Zinc oxide
Time (hs)
%Yieldb
1
2
3
4
5
5
5
5
4
3
45
52
60
Ferric sulfate
65
compounds can also act as neuroprotectants, platelet anti-aggregators, cerebral
Aluminium sulfate
92
12-15
anti-ischemic agents and chemosensitizers
.
The remarkably diverse
activities of these compounds has attracted many chemists to attempt to
synthesize this heterocyclic nucleus.
a: Reaction conditions ethyl acetoacetate (1mmol), dimedone(1mmol),
benzaldehyde (1mmol) and ammonium acetate (1.5mmol) EtOH reflux b:
isolated yield
The classical method for the synthesis of 4-aryl-1,4-dihydropyridine
involves mixing aldehyde with ethyl acetoacetate and ammonia in acetic acid
or in refluxing alcohol 16. However, this method has several disadvantages
including longer reaction times, the us of an excess amount of organic solvent,
lower product yields and harsh refluxing conditions. Since the method of
Hantzsch was described more than a use century ago 17-19, several efficient
methods have been developed for the synthesis of 1, 4-dihydropyridines that
involve the use of a microwave 20-22, ionic liquids 23-24, high temperatures in
refluxing solvent 25-35, TMSCl-NaI 36 and metal triflates 37. However, the use of
high temperatures, expensive metal precursors and the resultant longer reaction
times limit these methods. Thus, the development of a simple, efficient and
versatile method for the preparation of 1,4-dihydropyridine derivatives is an
active area of research and there is room for further improvement, namely
using milder reaction conditions and resulting in higher product yields.
Aluminium sulfate, with its mild acidity, involatility and incorrositivity, is
insoluble in common organic solvents; therefore, the use of aluminium sulfate
in organic synthesis is very limited. Here, we report the use of aluminium sulfate
as a catalyst for the multicomponent Hantzsch reaction. Our results demonstrate
that aluminium sulfate is a very effective, environmentally friendly catalyst for
the four-component condensation of ethyl acetoacetate, diemedone, aromatic
aldehyde and ammonium acetate to form a polyhydroquinoline derivative in
high yield.
Our initial experiments focused on the optimization of the amount of
Al (SO4)3 by using the ratio 1 equivalent of ethyl acetoacetate, 1 equivalent
of 2dimedone, 1 equivalent of benzaldehyde and 1.5 equivalent of ammonium
acetate and variable amount of Al2(SO ) . We observed that 20 mole % of
Al (SO4)3 could effectively catalyze the4r3eaction and increase the amount of
Al22(SO ) to 30 mol % with no substantial improvement in the yield. ( Table
2 entry413-6 ) .
Table 2 Synthesis of Polyhydroquinoline derivative under different
conditionsa
Entry
Al2(SO4)3 mol %
Time hrs
%Yieldb
42
1
2
3
4
5
6
No catalyst
24
20
8
5
56
10
15
20
30
75
6
80
4
92
4
93
RESULTS AND DISCUSSION
a: Reaction conditions ethyl acetoacetate (1mmol), dimedone(1mmol),
benzaldehyde (1mmol) and ammonium acetate (1.5mmol) EtOH reflux b:
isolated yield
In the initial experiments we screened common Lewis acids for their
ability to catalyze the Hantzsch reaction. To study the feasibility of the common
Lewis acids, the reaction of ethyl acetoacetate, dimedone, benzaldehyde and
ammonium acetate was selected as a model. The common Lewis acids such
as silicotungstanic acid, stannous chloride, zinc oxide, ferric sulfate produce
low yield. However, among the common Lewis acids studied for this reaction,
aluminium sulfate was found to be the most effective catalyst as it resulted in
the highest conversion of ethyl acetoacetate into polyhydroquinoline. ( Table
1 entry 5).
In an effort to obtain improved yields, three solvents were screened in
the Hantzsch reaction of ethyl acetoacetate, dimedone, benzaldehyde and
ammonium acetate at reflux condition and the results are summarized in Table
3. Ethanol provided excellent yields and proved to be the solvent of choice,
whereas acetic acid afforded lower yield. The reaction in water afforded very
poor yield.
e-mail address: pramodskulkarni3@gmail.com
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J. Chil. Chem. Soc., 59, Nº 1 (2014)
Table 3 Al2(SO4)3 catalyzed Hantzsch reaction in different solvent
It follows from Table 4 that yields of all the products are good to excellent
and a variety of functionalities such as nitro, halide, ether and hydroxyl can
be accommodated in polyhydroquinoline derivatives. Aromatic aldehydes
carrying electron withdrawing substituent’s reacted in shorter reaction time
with excellent yields to give polyhydroquinoline compared to the presence of
electron donating groups in aromatic aldehydes.
Entry
Solvent
EtOH
%Yield
92
1
2
3
Acetic acid
Water
65
25
These results encouraged us to extend this method to synthesize other
substituted polyhydroquinoline. All yields were those of isolated products after
purification and are comparable to the best overall yields previously reported
for the appropriate polyhydroquinoline products. The structures of the products
were confirmed from melting point and spectroscopic data.
Figure 1 Al2(SO4)3 catalyzed synthesis of Polyhydroquinoline derivatives
Table 4 Al2(SO4)3 catalyzed synthesis of Polyhydroquinoline derivatives through Hantzsch reactiona
Entry
1
2
2a
2b
2c
2d
2e
2f
Ar
C6H5
Time (hr)
Product
5a
% Yield
92
Mp(°C)
203-205
254-256
233-236
248-250
158-160
198-200
206-209
250-254
230-233
198-200
240-243
207-209
230-234
256-258
236-238
4
5
3
5
6
4
6
5
5
5
5
4
5
5
5
2
4-MeOC6H4
4-HOC6H4
5b
5c
88
3
91
4
3,4-(OH)2C6H3
2,5-(OMe)2C6H3
3,4,5-(MeO)3C6H2
4-HO-3-CH3O-C6H3
4-Br C6H4
5d
5e
86
5
85
6
5f
89
7
2g
2h
2i
5g
5h
5i
87
8
89
9
4-Cl C6H4
87
10
11
12
13
14
15
2j
4-F C6H4
5j
91
2k
2l
4-NO2 C6H4
2-NO2 C6H4
3,4-(OMe)2C6H3
4-Me C6H4
5k
5l
91
83
2m
2n
2o
5m
5n
5o
89
86
2-Br C6H4
79
a: Reaction conditions ethyl acetoacetate (1mmol), dimedone(1mmol), benzaldehyde (1mmol) and ammonium acetate (1.5mmol), Al2(SO4)3 (0.1mmol) EtOH
reflux b: isolated yield
Role of aluminium sulfate in this reaction is to activate the aldehyde by
binding of aluminium sulfate with the oxygen atom which ultimately enhances
the electrophilicity of the aldehyde and leads to a decrease in reaction time.
yields, an ecofriendly procedure, shorter reaction times and a simple work-up
procedure.
EXPERIMENTAL
General Procedures
Aluminium sulfate is purchased from loba chemicals. All the yields
were calculated from crystallized products. Melting points of the compounds
were determined in open capillary tubes and are uncorrected. IR spectra
were recorded on a Perkin-Elmer FTIR-1710 spectrophotometer. 1H NMR
and 13C NMR spectra were recorded at room temperature on Bruker AC-250
spectrometers using TMS as internal standard.
General Procedure for the synthesis of polyhydroquinoline
A mixture of dimedone (2mmol), aromatic aldehyde (2mmol),ethyl
acetoacetate(2mmol), ammonium acetate (4mmol) and 10% aluminium sulfate
was refluxed in ethanol for the time as mentioned in Table 4. The progress of
reaction was monitored by TLC. After completion of reaction, the reaction
mixture was poured into crushed ice and the solid product was separated,
filtered and recrystallized from ethanol to get pure yellow or white
coloured crystalline polyhydroquinoline derivative 5a-5o.
Figure 1: Mechanism of Aluminium Sulfate catalyzed synthesis of
Polyhydroquinoline
CONCLUSION
We have described a simple and general method for the synthesis of
polyhydroquinoline by using aluminium sulfate a solid acid catalyst, which
has many advantages such as inexpensive and easily available, easy to handle,
reusability, recovery, insoluble in most organic solvents, being eco-friendly and
green process catalysts. The method offers several advantages including high
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