Triton-X-100 catalyzed synthesis of 1,4-dihydropyridines and their aromatization to pyridines and a new one pot synthesis of pyridines using visible light in aqueous media

Article abstract of DOI:10.1039/c3ra40706c

A realistic and convenient synthetic method has been developed for the facile synthesis of 1,4-dihydropyridine derivatives in the presence of the non-ionic surfactant Triton X-100, in an aqueous medium at room temperature. A greener method to synthesize pyridine derivatives has also been developed by the oxidation of 1,4-dihydropyridine derivatives with almost 100% yields and also in a one pot synthesis, employing an aldehyde, ethyl acetoacetate and ammonium acetate in an aqueous micellar medium by irradiation with potassium persulphate in the presence of visible light. The one pot protocol offered excellent yields of the targeted product in a very short period of time at room temperature and the non-ionic surfactant catalyst can be recovered very easily. We also observed that during the reaction there was the formation of micelles, or micelle-like colloidal aggregates, from the non-ionic surfactant and the reaction mixture in water, measured by dynamic light scattering and visualized through an optical microscope. The process is advantageous as ammonia is generated from an ammonium salt under absolutely neutral conditions and the product purification follows a group assistant purification chemistry process (GAP).

Full text of DOI:10.1039/c3ra40706c

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Triton-X-100 catalyzed synthesis of 1,4-
dihydropyridines and their aromatization to pyridines
and a new one pot synthesis of pyridines using visible
light in aqueous media3
Cite this: RSC Advances, 2013, 3, 8220
Received 8th February 2013,
Accepted 8th April 2013
DOI: 10.1039/c3ra40706c
Partha Pratim Ghosh, Prasun Mukherjee and Asish R. Das*
www.rsc.org/advances
A realistic and convenient synthetic method has been developed
for the facile synthesis of 1,4-dihydropyridine derivatives in the
presence of the non-ionic surfactant Triton X-100, in an aqueous
medium at room temperature. A greener method to synthesize
pyridine derivatives has also been developed by the oxidation of
1,4-dihydropyridine derivatives with almost 100% yields and also
in a one pot synthesis, employing an aldehyde, ethyl acetoacetate
and ammonium acetate in an aqueous micellar medium by
irradiation with potassium persulphate in the presence of visible
light. The one pot protocol offered excellent yields of the targeted
product in a very short period of time at room temperature and
the non-ionic surfactant catalyst can be recovered very easily. We
also observed that during the reaction there was the formation of
micelles, or micelle-like colloidal aggregates, from the non-ionic
surfactant and the reaction mixture in water, measured by
dynamic light scattering and visualized through an optical
microscope. The process is advantageous as ammonia is gener-
ated from an ammonium salt under absolutely neutral conditions
and the product purification follows a group assistant purification
chemistry process (GAP).
to the poor solubility of the organic compounds. A possible new
way to improve the solubility of substrates is the use of surface-
active compounds that can form micelles.3
Under ambient conditions, surfactant molecules can aggregate
in an aqueous phase to form micelles with a hydrophobic core
and a hydrophilic corona. Lewis acidic or basic surfactant
catalyzed reactions are commonly reported, but there are very
few reports where non-ionic surfactants were used as the catalyst.4
Non-ionic surfactants have the tendency to adsorb at interfaces
and to form micelles, otherwise, their critical micelle concentra-
tion (CMC) is similar to the ionic surfactants.5 However, the
benefit of non-ionic surfactants (e.g. Triton X-100) is the absence of
the electrical double layer, as formed by the ionic surfactants.
Therefore, non-ionic surfactants are necessary model adsorbents
for interfacial processes. Hence, we planned to utilize these
properties of non-ionic surfactant for our present study.
In recent years, the swift assembly of molecular diversity is an
important goal of synthetic organic chemistry and one of the key
patterns of modern drug discovery. The tactics to address this
contest involve the development of multicomponent reactions
(MCRs), in which three or more reactants are combined together
in a single reaction flask, to generate a product incorporating most
of the atoms contained in the starting materials. In addition,
MCRs in water are one of the most powerful tools for the atom
efficient, time minimized, cost-advantageous and environmentally
waste-free synthesis of bioactive motifs.6
Functionalized pyridine and 1,4-dihydropyridine derivatives
have long been known as important biologically active com-
pounds. 1,4-Dihydropyridines have been extensively used as
calcium channel modulators,7 and were developed as cardiovas-
cular, antihypertensive and anticancer drugs, which include
diludine, felodipine, isradipine, lacidipine, nitrendipine, nifedi-
pine and nemadipine B (Fig. 1)8 and their oxidized counterparts
target a wide variety of biological receptors.9 Due to the existence
of pyridines in pharmaceuticals, agrochemicals, and natural
products, their synthesis remains an area of intense current
interest to the chemical community.10 The corresponding
pyridines of Hantzsch 1,4-dihydropyridines have been extensively
studied in view of the significance of this reaction to the
Introduction
Developing environmentally benign and economical syntheses is
an active area of research that is being willingly pursued, and the
avoidance of hazardous organic solvents follows the fundamental
strategy to achieve the efficacy. The most attractive alternative to
organic solvents is water, which has a perceived increasing
popularity, due to being cheap and readily available, which have
become major concerns in academia and industry and the need
for green reactions is now globally putative.1 In addition, reactions
in aqueous media illustrate distinctive reactivities and unique
selectivities that are not usually observed in organic media.2
However, organic reactions in water are often limited in scope due
Department of Chemistry, University of Calcutta, Kolkata-700009, India.
E-mail: ardchem@caluniv.ac.in; ardas66@rediffmail.com; Fax: +913323519754;
Tel: +913323501014 Tel: +919433120265
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra40706c
3
8220 | RSC Adv., 2013, 3, 8220–8226
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Communication
Scheme 1 One pot synthesis of 1,4-dihydropyridine, pyridine and the conversion
Fig. 1 Some bioactive dihydropyridines.
of 1,4-dihydropyridine to pyridine.
metabolism of Hantzsch esters and to study the biologically
important NADH redox processes.11
catalyst (Table 1, entry 3). While the use of a cationic surfactant
CTAB (cetyl trimethylammonium bromide) as a catalyst in
aqueous media, provided a slight higher yield than the anionic
surfactant (Table 1, entry 4) of the desired product. We then
applied a non-ionic surfactant, Triton X-100 (10 mol%) as the
catalyst in water. Eventually we achieved satisfaction because the
reaction proceeded well, affording the desired product in a 96%
yield within 2.5 h (Table 1, entry 5). Triton X-100 played an
amazing catalytic role in this particular MCR in comparison to the
other surfactants applied, which can be attributed to its high
solubilizing capacity related to its hydrophobic character; in
addition, the surfactant properties of Triton X-100 improve the
reaction kinetics by increasing the interfacial area and also the
aggregation number of the micelles. For the present investigation
of micellar systems, the aggregation number follows the trend:
A variety of methods have been materialized to achieve the
synthesis of this dihydropyridine and the pyridine nucleus.
Despite some progress, most of the methods12–16 suffer from a
number of disadvantages, like using organic solvents, acidic
reaction conditions, high reaction temperatures and low catalytic
efficiencies. Surprisingly, very little is known about the surfactant
catalyzed synthesis and light induced oxidations of 1,4-dihydro-
pyridines and the one pot synthesis of pyridine derivatives.
Our group is involved in the utilization of visible light in
chemical reactions, involving water as a reaction medium in
organic multicomponent reactions (MCRs)17 for the synthesis of
various biologically important heterocyclic compounds. We wish
to report herein a highly efficient procedure for the preparation of
1,4-dihydropyridine derivatives via a one pot, four component
Hantzsch reaction,18 using the non-ionic surfactant Triton X-100
in aqueous media at room temperature and a conceptually
distinct approach to the synthesis of highly substituted pyridines
via a one pot, three component reaction and oxidation of 1,4-DHP
to the corresponding pyridines, with almost 100% yields within
very few minutes. This approach is based upon the light induced
synthesis of 1,4-dihydropyridine and its oxidation to the corre-
sponding pyridines in the presence of potassium persulphate,
K2S2O8 (1 mmol) and Triton X-100 (10 mol%) in water at room
temperature (Scheme 1).
Triton X-100 (Nagg = 14319) . CTAB (Nagg = 9220) . SDS (Nagg
=
6021). An increase in the aggregation number results in an increase
in the surface charge of the micellar units, which can subsequently
create ambient conditions which optimize the reaction purity,
yield and speed for the reaction to move forward.
Having evaluated Triton X-100 as the right choice of catalyst for
the experiment, we then concentrated our attention on designing
and also generalizing the promising conditions for the reaction.
We firstly attempted some screening tests with Triton X-100. The
quantity of the catalyst had a large effect on the formation of the
desired product. The use of 15 mol% Triton X-100 diminished the
quantity of the yield, whereas the yield of the product was much
decreased when we used 5 mol% Triton X-100 (Table 1, entries 6
and 7). The yields of the desired product were also decreased when
Triton X-100 was refluxed with water (Table 1, entry 8). Water
showed superiority to the other solvents tested [ethanol (Table 1,
entry 9), chloroform (Table 1, entry 10) and acetonitrile (Table 1,
entry 11)], while under the solvent-free conditions (Table 1, entry
12) at room temperature, Triton X-100 failed to provide satisfactory
outputs. Therefore, water was chosen as the solvent for this
reaction as the maximum yield (96%) was obtained under
aqueous conditions. Hence, these optimized conditions were
followed for all experiments: taking 3-nitrobenzaldehyde (1 mmol),
ethyl acetoacetate (2 mmol) and ammonium acetate (1.5 mmol) in
the presence of 10 mol% Triton X-100 in aqueous media at room
Results and discussion
In order to optimize the reaction conditions and identify the best
surfactant catalysts, the reaction was studied by employing
surfactant catalysts with solvents, as well as under solvent-free
conditions, with the hope of maximizing the product yield in short
reaction times (Table 1). In our initial studies, we used
3-nitrobenzaldehyde 1 (1 mmol), ethyl acetoacetate 2 (2 mmol)
and ammonium acetate 3 (1.5 mmol) as model substrates
(Scheme 1) and these were stirred at room temperature in the
presence of H2O and ethanol as the solvents, without any catalyst.
However, even after 24 h, the reaction failed to afford any product
(Table 1, entries 1 and 2). The reactions were also restrained by
using the anionic surfactant SDS (sodium dodecyl sulphate) as the
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 8220–8226 | 8221

View Article Online
Communication
RSC Advances
Table 1 Screening of catalyst and solvents and reaction conditionsa
Entry
Catalysts
Solvents
Conditions
Time (h)
Yieldsb (%)
c
1
2
3
4
5
6
7
8
—
—
H2O
EtOH
H2O
H2O
H2O
H2O
H2O
H2O
EtOH
CHCl3
CH3CN
—
RT
RT
RT
RT
RT
RT
RT
reflux
RT
RT
RT
RT
24
24
24
24
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
—
—
c
SDS (10 mol%)
CTAB (10 mol%)
24
41
96
86
81
66
54
59
44
32
Triton-X-100 (10 mol%)
Triton-X-100 (15mol%)
Triton-X-100 (5mol%)
Triton-X-100 (10 mol%)
Triton-X-100 (10 mol%)
Triton-X-100 (10 mol%)
Triton-X-100 (10 mol%)
Triton-X-100 (10 mol%)
9
10
11
12
a
All reactions were carried out with m-nitrobenzaldehyde (1 mmol), ethyl acetoacetate (1 mmol) and ammonium acetate (1.5 mmol) in 3 ml
b
c
solvent. Yield of isolated product. Reaction failed to provide any product.
temperature (Scheme 1). Typically, a mixture of the substituted
aldehyde (1.0 mmol), ethyl acetoacetate (2.0 mmol), ammonium
acetate (1.5 mmol) and 10 mol% Triton X-100 in 3 ml water was
stirred at room temperature for 2–3.5 h, which afforded a library of
1,4-dihydropyridines (4a–z) and polyhydroquinolines (5) deriva-
tives in good to excellent yields (83–96%) (Table 2).
The optimum conditions were 1,4-dihydropyridines in the
presence of potassium persulphate, K2S2O8 (1 mmol) and Triton
X-100 (10 mol%) in water, irradiated with visible light at room
temperature. The results obtained with various 1,4-dihydropyr-
idines are given in Table 3.
Further experiments demonstrated that pyridine derivatives
can be produced instead of dihydropyridines, when the reagents
are irradiated with potassium persulphate in a one pot reaction, in
The scope of this study was then successfully extended to the
oxidation of 1,4-dihydropyridine in water with almost 100% yields.
Table 2 Substrates scope for the synthesis of 1,4-dihydropyridine(4a–4z)
Entry
R
1,3-Diketones
Time (h)
Product
Yield (%)a
1
2
3
4
5
6
7
8
C6H5
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Acetyl acetone
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Acetyl acetone
Acetyl acetone
Acetyl acetone
Acetyl acetone
Acetyl acetone
Acetyl acetone
Acetyl acetone
Acetyl acetone
Acetyl acetone
2.5
2.5
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
95
96
93
89
94
95
96
95
88
85
83
90
91
90
85
87
89
88
87
88
87
84
92
90
87
88
3-NO2C6H4
4-MeOC6H4
4-HOC6H4
4-ClC6H4
4-FC6H4
2-Furyl
H
3
2.5
2.5
2
2
9
n-Propyl
2.5
2.5
3.5
3
2.5
2.5
3.5
3.5
3
2.5
2.5
2.5
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2-Pyridyl
4-Me2NC6H4
3-NO2C6H4
2,3-Cl2C6H3
C6H5
4-MeOC6H4
4-HOC6H4
4-ClC6H4
2-Furyl
n-Propyl
4-NO2C6H4
4-FC6H4
4-OMeC6H4
4-NO2C6H4
4-MeOC6H4
4-NO2C6H4
4-MeOC6H4
Acetyl acetone
Acetyl acetone
Acetyl acetone
Acetyl acetone
Acetyl acetone
4s
4t
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Dimedone
Dimedone
Dimedone
4u
4v
4w
4x
4y
4z
3
Ethyl acetoacetate
Ethyl acetoacetate
Acetyl acetone
3.5
3.5
3.5
3.5
Dimedone
Acetyl acetone
a
Isolated yield of the pure compound.
8222 | RSC Adv., 2013, 3, 8220–8226
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Communication
Table 3 Substrate scope for the oxidation of 1,4-dihydropyridine to pyridines
(5a–5g).
Entry
R
R1
Product(s) Time (min) Yields (%)a
1
2
3
4
5
6
7
H
OEt 5a
OEt 5b
OEt 5c
15
15
20
20
15
20
20
y100
y100
y100
y100
y100
y100
y100
Fig. 2 DLS study of the reaction media showing formation of aggregates.
4-NO2C6H4
3-NO2C6H4
4-MeOC6H4 OEt 5d
4-MeC6H4
4-ClC6H4
C6H5
OEt 5e
OEt 5f
OEt 5g
activity (recovery amount 91% and yield 87%, after the 5th run).
The reactions were consistently carried out at the 1 mmol scale
and no change of product yield was observed when scaled up to
the 10 mmol scale at room temperature. The catalytic effect of
micellar Triton X-100 in this reaction can be explained as follows:
in the micellar solution, ethyl acetoacetate, aldehyde and
ammonium acetate which are all hydrophobic, are forced inside
the hydrophobic core of the micelles, thus allowing the reaction to
take place more easily.
a
Yield of the isolated products.
the presence of visible light with high yields, in a short period of
time (Table 4). The structure of the 1,4-dihydropyridines and
pyridines were confirmed by comparing their physical and spectral
data with their reference data or elucidated by NMR spectroscopy
It is significant to mention that the addition of Triton X-100 in
the reaction flask converted the initially suspended reaction mass
into a homogeneous mixture, which on stirring became a
yellowish turbid emulsion. This observation implies that there
was formation of micelles or micelle-like colloidal aggregations.
The average sizes of the colloidal particles formed from the non-
ionic surfactant and the reaction mixture in water were measured
by dynamic light scattering, and appeared to be about 100 nm in
diameter (Fig. 2). Fig. 3 shows optical microscope (406) images in
the 10 mol% Triton X-100 and 3 ml water system of the reaction
mixture; round structures can be clearly observed. As shown in the
polarizing microscope image in Fig. 3a (before the addition of
potassium persulphate) and Fig. 3b (after the addition of
(ESI ).
3
To test the generality of this reaction, a series of aromatic,
aliphatic and heteroaromatic aldehydes were subjected to the
optimal reaction conditions (Table 2). Ethyl acetoacetate, acetyl
acetone and dimedone were also used for forming the dihydro-
pyridine ring with ammonium acetate (acting as the ammonia
donor), to access the corresponding 1,4-dihydropyridine deriva-
tives. The reactions proceeded smoothly and provided excellent
yields and tolerated unsubstituted benzaldehydes, and both
electron-withdrawing and electron-donating para-substituted ben-
zaldehydes.
The reusability of the catalyst was studied through the
condensation of 3-nitrobenzaldehyde, ethyl acetoacetate and
ammonium acetate. Upon completion of the reaction, the product
was filtered and washed with water and the unused starting
materials were extracted using diethyl ether and the separated
micellar media were reused for the next cycle. The recycling could
be followed five consecutive times with almost unaltered catalytic
Table 4 Substrates scope for the one pot synthesis of pyridines (5a–5g)
Entry
R
R1
Product
Time (h)
Yields (%)a
1
2
3
4
5
6
7
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
5a
5b
5c
5d
5e
5f
2
2
2.5
3
2
2.5
2.5
80
77
80
80
77
82
78
4-NO2C6H4
3-NO2C6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
C6H5
Fig. 3 Optical microscope images (25 mm at 406) of nano-vesicle structures
forming in emulsion samples: (a) without the addition of K2S2O8 solution; (b) 15
min, (c) 1.5 h and (d) 2.5 h after K2S2O8 addition.
5g
a
Yield of the isolated product.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 8220–8226 | 8223

View Article Online
Communication
RSC Advances
potassium persulphate), only the shell part of the round structures
is gleaming. Furthermore, we observed the growth process of
these vesicles with the reaction progress over time, using the
microscope. Before forming a vesicle, a cylindrical micellar-like
structure was formed (Fig. 3c). It closed slowly and finally became
spherical (Fig. 3d). The emulsion formation is attributed to the
property of Triton X-100 as a surfactant, and this property should
be important to accelerate the reaction rate. That is, these colloidal
vesicles would function as effective reaction domains in water. The
driving force of the reaction in the presence of micelles may be
related to the hydrophobic forces which compress the reactants
together in a highly compact arrangement of complexes, within a
restricted hydrophobic domain.
Presumably, the reaction may proceed through the following
mechanistic pathway, which is presented in Scheme 2. Initially, a
Knoevenagel condensation occurs, by the coupling of the aldehyde
(1) with the active methylene group of one equivalent of
b-ketoester (2) to form intermediate (I). Then, intermediate (I)
readily undergoes a nucleophilic addition from the enol form of
the second equivalent of the b-ketoester, followed by a Michael
addition, to generate 1,5-dioxo compound (II) in the micellar
system. Ammonia and acetic acid generated from ammonium
acetate (3) in the presence of water at room temperature, convert
intermediate (II) into intermediate (III), which then undergoes a
cyclocondensation and generates 1,4-dihydropyridine (4), follow-
ing conventional acid catalysis (acetic acid from ammonium
acetate). An alternative reaction pathway, that remains
a
possibility, is via the formation of intermediate (IV), an enamine
ester, which is produced by the condensation of the second
equivalent of the b-ketoester with ammonia in the micellar system,
generates intermediate (III), following the condensation with
intermediate (I), finally affording 1,4-dihydropyridine (4). We
attempted to isolate; (i) intermediate (I) from the two component
reaction of ethyl acetoacetate and 4-nitrobenzaldehyde (1 : 1), (ii)
intermediate (II) from the three component reaction of ethyl
acetoacetate and 4-nitrobenzaldehyde (2 : 1) and (iii) intermediate
(IV), from the two component reaction between ethyl acetoacetate
and ammonium acetate in the aqueous micellar system (in the
presence of a catalytic amount of ammonium acetate (10 mol%)).
Unfortunately, all these attempts produced no trace of the desired
intermediates. The analysis of these results revealed that the
intermediates (I), (II) and (IV) are very reactive towards the
subsequent reaction under multicomponent reaction conditions
in the micellar system. Consequently, whether the sequential
reactions occur through the intermediate (I), (II) or (IV) could not
be ascertained and evaluated in the present study. During the
oxidation of 1,4-dihydropyridine derivatives, we used potassium
persulphate, K2S2O8, which is not a photocatalyst, however,
22
photolysis of S2O8
produces two sulphate radical anions
(SO42) with a quantum efficiency of unity,22 and the formed
SO4 can act as a strong oxidant in aqueous systems: initially a
2
one electron transfer from 1,4-dihydropyridine to the radical anion
(SO42) gives a radical cation (IV), which loses a proton to form
intermediate (V). Again a one electron transfer to the sulfate
radical anion (SO42), to form the intermediate (VI), subsequently
results in the aromatized product (5) by homolysis.
It is also interesting to mention that for the one pot synthesis
of pyridine, the sulphate radical anion did not oxidize the
aldehyde, rather the reaction takes the desired course and pyridine
derivatives are the sole isolable products under the attempted
micellar reaction conditions.
From the stand point of green chemistry, it was positive to find
that the final products could be isolated by filtration at the end of
the reaction, due to their lower solubility in the TritonX-100–water
mixture. Furthermore, their purity was high and did not require
their preparation in an analytically pure form by single
recrystallization, thus avoiding extraction steps and chromato-
graphic separations. Therefore, we preferred water as the reaction
medium over unsafe organic solvents, which decreased the
chemical impurities, afforded an easy work-up procedure and
avoided producing large volumes of waste from the discarded
chromatographic static phases. Aromatic aldehydes with electron-
donating and electron-withdrawing groups both participated in
this reaction equally well; apparently, the nature and position of
substitution on the aryl ring do not make much difference in
reactivity. Similarly, aliphatic (Table 2, entries 8, 9 and 19) and
heterocyclic aldehydes (Table 2, entries 7, 10 and 18) afforded
excellent yields of the products, without forming any side-
products.
Scheme 2 Plausible mechanism for the formation of 1,4-dihydropyridine and the
corresponding pyridine.
8224 | RSC Adv., 2013, 3, 8220–8226
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Communication
completion of the reaction (indicated by TLC), the free flowing
solids were filtered and washed with water (20 ml) to afford the
desired products as pale yellow solids. The products thus obtained
were recrystallized from ethanol to get pure compounds as white
or pale yellow crystals.
Conclusions
In summary, a practical and convenient synthetic method in
aqueous media using Triton X-100 as the surfactant catalyst (10
mol%) has been developed, for the facile synthesis of 1,4-
dihydropyridines and polyhydroquinolines. We have also success-
fully developed a new and easy to perform method for the efficient
oxidation of Hantzsch 1,4-dihydropyridines and a new one pot
potentially efficient, absolutely clean, versatile, environment-
friendly, light induced, green procedure for the synthesis of
pyridines. The operational simplicity and excellent yields of the
products in a short period of time at room temperature are the
main advantages of this method, and furthermore, this procedure
is cheap, safe and environmentally benign which makes this
methodology a superior approach for the preparation of small
molecules of medicinal concern.
Acknowledgements
We gratefully acknowledge the financial support from U. G. C.
and Calcutta University. P. P. G. thanks U. G. C, New Delhi,
India for the grant of his Senior Research Fellowship. P. M.
thanks U. G. C, New Delhi, India for the grant of his Junior
Research Fellowship. We are thankful to Mr. Sumanta Kumar
Ghatak for his cooperation.
References
1 (a) A. Kumar and S. Sharma, Green Chem., 2011, 13, 2017; (b)
A. Kumar, G. Gupta and S. Srivastava, Green Chem., 2011, 13,
245; (c) A. Kumar, M. K. Gupta and M. Kumar, Green Chem.,
2012, 14, 290; (d) K. Tanaka, T. Sugino and F. Toda, Green
Chem., 2000, 2, 303; (e) C. L. Raston and J. L. Scott, Green Chem.,
2000, 2, 49.
2 (a) S. Kobayashi, Y. Mori, S. Nogayama and K. Manabe, Green
Chem., 1999, 1, 175; (b) B. Cornils, Angew. Chem., Int. Ed. Engl.,
1995, 34, 1575.
3 (a) J. H. Fendler and E. J. Fendler, Catalysis in Micellar and
Macromolecular Systems, Academic Press, London, 1975; (b)
Mixed Surfactant Systems, ed. P. M. Holland and D. N. Rubingh,
ACS, Washington, DC, 1992; (c) Structure and Reactivity in
Aqueous Solution, ed. C. J. Cramer and D. G. Truhlar, ACS,
Washington, DC, 1994; (d) Surfactant-Enhanced Subsurface
Remediation, ed. D. A. Sabatini, R. C. Knox and J. H. Harwell,
ACS, Washington, DC, 1994.
Experimental
General procedure for the preparation of 1,4-dihydropyridines
(4a–4z)
The aldehyde (1) (1 mmol), 1,3-diketone (2) (2 mmol) and
ammonium acetate (3) (1.5 mmol) were added to a solution of
Triton X-100 (10 mol%) in H2O (3 mL), and the mixture stirred at
room temperature. The resulting clear solution, that gradually
became turbid, was stirred for the stipulated time mentioned in
Table 2. After completion of the reaction (indicated by TLC), the
free flowing solid mass was filtered and washed with water (20 ml)
to afford the desired products as pale yellow solids. The products
thus obtained were recrystallized from ethanol to give pure
compounds as white or pale yellow crystals.
General procedure for the oxidation of 1,4-dihydropyridines to
the corresponding pyridines (5a–5g)
4 (a) A. Bhattacharya, V. Purohit and F. Rinaldi, Org. Process Res.
Dev., 2003, 7, 254; (b) A. Kumar, M. K. Gupta and M. Kumar,
Tetrahedron Lett., 2010, 51, 1582; (c) A. Kumar, M. K. Gupta and
M. Kumar, Tetrahedron Lett., 2011, 52, 4521.
5 X. Zeng and K. Osseo-Asare, J. Colloid Interface Sci., 2004, 272,
298.
6 (a) A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725; (b) M.
C. Pirrung and K. D. Sarma, J. Am. Chem. Soc., 2004, 126, 444; (c)
C. J. Li, Chem. Rev., 1993, 93, 2023; (d) C. J. Li, Chem. Rev., 2005,
105, 3095; (e) K. Tanaka and F. Toda, Chem. Rev., 2000, 100,
1025.
7 (a) J. A. Joule and K. Mills, Heterocyclic Chemistry, 4th edn.
Blackwell, Oxford, UK, 2000; (b) D. Triggle, Cell. Mol. Neurobiol.,
2003, 23, 293.
A solution of 1,4-dihydropyridine (1 mmol) in Triton-X-100 (10
mol%) in 3 mL water was contained in a 25 mL glass vessel and
potassium persulphate (1 mmol) was added. The reaction vessel
was placed 10 cm away from the visible light source (150 W
tungsten lamp of Philips, with a cut-off light filter to allow only l
. 300 nm), which had a water circulation jacket, maintaining the
temperature of the reaction mixture at 25 uC for the required
period of time (indicated by TLC) (temperature inside the flask 25
uC). After completion of the reaction, the free flowing solid was
filtered off and washed with water (20 mL) to afford the desired
product with almost 100% yield.
8 (a) B. Love, M. Goodman, K. Snader, R. Tedeschi and E. Macko,
J. Med. Chem., 1974, 17, 956; (b) F. Bossert, H. Meyer and
E. Wehinger, Angew. Chem., Int. Ed. Engl., 1981, 20, 762; (c)
S. Goldmann and J. Stoltefuss, Angew. Chem., Int. Ed. Engl.,
1991, 30, 1559; (d) R. H. Fagard, J. Clin. Basic Cardio., 1999, 2,
163; (e) V. Klusa, Drugs Future, 1995, 20, 135; (f) I. O. Donkor,
X. Zhou, J. Schmidt, K. C. Agrawal and V. Kishore, Bioorg. Med.
Chem., 1998, 6, 563; (g) T. Godfraid, R. Miller and M. Wibo,
Pharmocol. Rev., 1986, 38, 321; (h) R. G. Bretzel, C. C. Bollen,
E. Maeser and K. F. Federlin, Am. J. Kidney Dis., 1993, 21, 53; (i)
R. G. Bretzel, C. C. Bollen, E. Maeser and K. F. Federlin, Drugs
Future, 1992, 17, 465; (j) R. Boer and V. Gekeler, Drugs Future,
1995, 20, 499.
General procedure for the one pot synthesis of pyridines (5a–
5g)
A solution of aldehyde (1) (1 mmol), ethyl acetoacetate (2) (2
mmol) and ammonium acetate (3) (1.5 mmol) in Triton-X-100 (10
mol%) in 3 mL water was taken in a 25 mL glass vessel and to this
potassium persulphate (1 mmol) was added. The reaction vessel
was placed 10 cm away from the visible light source (150 W
tungsten lamp of Philips, with a cut-off light filter to allow only l
. 300 nm), which had a water circulation jacket, maintaining the
temperature of the reaction mixture at 25 uC for the required
period of time (temperature inside the flask 25 uC). After
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 8220–8226 | 8225

View Article Online
Communication
RSC Advances
9 G. D. Henry, Tetrahedron, 2004, 60, 6043.
and N. Mart|n, Magn. Reson. Chem., 2006, 44, 637; (b) S.
S. Katkarm, P. H. Mohiteb, S. Lakshman, L. S. Gadekara, B.
R. Arbada and M. K. Landea, Green Chem. Lett. Rev., 2010, 3,
287.
10 (a) D. A. Colby, R. G. Bergman and J. A. Ellman, J. Am. Chem.
Soc., 2008, 130, 3645; (b) J. Barluenga, M. A. Fernandez-
Rodr|guez, P. Garc|a-Garc|a and E. Aguilar, J. Am. Chem. Soc.,
2008, 130, 2764; (c) K. Parthasarathy, M. Jeganmohan and C.
H. Cheng, Org. Lett., 2008, 10, 325; (d) J. Dash, T. Lechel and H.
U. Reissig, Org. Lett., 2007, 9, 5541; (e) M. Movassaghi, M.
D. Hill and O. K. Ahmad, J. Am. Chem. Soc., 2007, 129, 10096; (f)
B. M. Trost and A. C. Gutierrez, Org. Lett., 2007, 9, 1473; (g) M.
D. Fletcher, T. E. Hurst, T. J. Miles and C. J. Moody,
Tetrahedron, 2006, 62, 5454; (h) M. Movassaghi and M.
D. Hill, J. Am. Chem. Soc., 2006, 128, 4592; (i) K. Tanaka,
N. Suzuki and G. Nishida, Eur. J. Org. Chem., 2006, 3917; (j)
Y. Yamamoto, K. Kinpara, R. Ogawa, H. Nishiyama and K. Itoh,
Chem.–Eur. J., 2006, 12, 5618; (k) M. M. McCormick, H.
A. Duong, G. Zuo and J. Louie, J. Am. Chem. Soc., 2005, 127,
5030.
15 (a) T. Itoh, K. Nagata, Y. Matsuya, M. Miyazaki and A. Ohsawa,
J. Org. Chem., 1997, 62, 3582; (b) J. R. Pfister, Synthesis, 1990,
689; (c) G. Sabitha, G. S. K. K. Reddy, C. S. Reddy, N. Fatima and
J. S. Yadav, Synthesis, 2003, 1267; (d) J. J. V. Eynde, A. Mayence
and A. Maquestiau, Tetrahedron, 1992, 48, 463; (e) M. C. Bagley
and M. C. Lubinu, Synthesis, 2006, 1283; (f) A. Singer and S.
M. McElvan, in Org.Synth., Coll. Vol., ed. A. H. Blatt, John Wiley
and Sons, New York, 11th edn, 1943, p. 214.
16 (a) M. M. Heravi, F. K. Behbahani, H. A. Oskooie and R.
H. Shoar, Tetrahedron Lett., 2005, 46, 2775; (b) S. H. Mashraqui
and M. A. Karnik, Tetrahedron Lett., 1998, 39, 4895; (c) M.
M. Hashemi and Y. Ahmadibeni, Monatsh. Chem., 2003, 134,
411; (d) N. Nakamichi, Y. Kawashita and M. Hayashi, Org. Lett.,
2002, 4, 3955; (e) B. Han, Z. Liu, Q. Liu, L. Yang, Z. L. Liu and
W. Yu, Tetrahedron, 2006, 62, 2492; (f) N. Nakamichi,
Y. Kawashita and M. Hayashi, Synthesis, 2004, 1015.
17 (a) P. P. Ghosh, S. Paul and A. R. Das, Tetrahedron Lett., 2013,
54, 138; (b) P. Bhattacharyya, S. Paul and A. R. Das, RSC Adv.,
2013, 3, 3203; (c) P. P. Ghosh, G. Pal, S. Paul and A. R. Das,
Green Chem., 2012, 14, 2691; (d) S. Paul, P. Bhattacharyya and A.
R. Das, Tetrahedron Lett., 2011, 52, 4636; (e) P. P. Ghosh and A.
R. Das, Tetrahedron Lett., 2012, 53, 3140; (f) P. Bhattacharyya,
K. Pradhan, S. Paul and A. R. Das, Tetrahedron Lett., 2012, 53,
4687; (g) K. Pradhan, P. Bhattacharyya, S. Paul and A. R. Das,
Tetrahedron Lett., 2012, 53, 5840; (h) S. Paul and A. R. Das,
Tetrahedron Lett., 2012, 53, 2206; (i) S. Paul and A. R. Das,
Tetrahedron Lett., 2013, 54, 1149.
11 (a) R. A. Janis and D. J. Triggle, J. Med. Chem., 1983, 26, 775; (b)
M. F. Gordeev, D. V. Patel and E. M. Gordon, J. Org. Chem.,
1996, 61, 924; (c) F. Bossert and W. Vater, Med. Res. Rev., 1989,
9, 291; (d) A. Sausins and G. Duburs, Heterocycles, 1988, 27, 269;
(e) R. J. Kill and D. A. Widdowson, in Biorganic Chemistry, ed. E.
E. van Tamelen, Academic Press, NY, 1978, 4, p. 239.
12 (a) H. Salehi and Q. X. Guo, Synth. Commun., 2004, 34, 4349; (b)
M. Li, W. S. Guo, L. R. Wen, Y. F. Li and H. Z. Yang, J. Mol.
Catal. A: Chem., 2006, 258, 133; (c) C. Chang, S. Cao, S. Kang,
L. Kal, X. Tian, P. Pandey, S. F. Dunne, C. H. Luan, D.
J. Surmeier and R. B. Silverman, Bioorg. Med. Chem., 2010, 18,
3147; (d) A. Debache, R. Boulcina, A. Belfaitah, S. Rhouati and
B. Carboni, Synlett, 2008, 509; (e) G. Sabitha, K. Arundhathi,
K. Sudhakar, B. S. Sastry and J. S. Yadav, Synth. Commun., 2009,
39, 2843; (f) J. -P. Wan and Y. Liu, RSC Adv., 2012, 2, 9763.
13 (a) G. W. Wang, J. J. Xia, C. B. Miao and X. L. Wu, Bull. Chem.
Soc. Jpn., 2006, 79, 454; (b) V. Sivamurugan, R. S. Kumar,
M. Palanichamy and V. J. Murugesan, J. Heterocycl. Chem., 2005,
42, 969; (c) J. L. Wang, B. K. Liu, C. Yin, Q. Wu and X. F. Lin,
Tetrahedron, 2011, 67, 2689; (d) H. Wu, X. -M. Chen, Y. Wan, H.
-Q. Xin, S. -Q. Lian and L. Ye, Asian J. Chem., 2009, 21, 2815; (e)
R. F. Affeldt, E. V. Benvenuttib and D. Russowsky, New J. Chem.,
2012, 36, 1502.
¨
18 A. Domling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168.
19 M. A. Partearroyo, A. Alonso, F. M. Goni, M. Tribout and
S. Paredes, J. Colloid Interface Sci., 1996, 178, 156.
20 K. Weidemaier, H. L. Tavernier and M. D. Fayer, J. Phys. Chem.
B, 1997, 101, 9352.
21 G. Saroja, B. Ramachandram, S. Saha and A. Samanta, J. Phys.
Chem. B, 1999, 103, 2906.
22 H. Hori, A. Yamamoto, E. Hayakawa, S. Taniyasu, N. Yamashita,
S. Kutsuna, H. Kiatagawa and R. Arakawa, Environ. Sci. Technol.,
2005, 39, 2383.
14 (a) S. Esperanza, M. Suarez, D. Molero, R. Mart|nez-Alvarez,
Y. Verdecia, E. E. Ochoa, A. Alvarez, C. C. Seoane, A. Herrera
8226 | RSC Adv., 2013, 3, 8220–8226
This journal is ß The Royal Society of Chemistry 2013