Sodium chloride: A proficient additive for the synthesis of pyridine derivatives in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2014.10.125

A facile and convenient synthesis of substituted pyridine derivatives catalysed by NaCl in the presence aqueous media under reflux and ultrasound irradiation has been developed via a one-pot multicomponent reaction, in which four new bonds were formed. Pa

Full text of DOI:10.1016/j.tetlet.2014.10.125

Accepted Manuscript
Sodium chloride: A proficient additive for the synthesis of pyridine derivatives
in aqueous medium
Jitendra B. Gujar, Mahendra A. Chaudhari, Deepak S. Kawade, Murlidhar S.
Shingare
PII:
S0040-4039(14)01832-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.125
TETL 45354
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 September 2014
22 October 2014
23 October 2014
Please cite this article as: Gujar, J.B., Chaudhari, M.A., Kawade, D.S., Shingare, M.S., Sodium chloride: A proficient
additive for the synthesis of pyridine derivatives in aqueous medium, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.10.125
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Sodium chloride: A proficient additive for the synthesis of pyridine derivatives in
aqueous medium.
Jitendra B. Gujar, Mahendra A. Chaudhari, Deepak S. Kawade and Murlidhar S. Shingare*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004,
Maharashtra, India
*Corresponding author
Tel.: +91 2402403311; Fax: +91 2402403113
E-mail address: prof_msshingare@rediffmail.com
Abstract:
A facile and convenient synthesis of substituted pyridine derivatives catalyzed by NaCl in the
presence aqueous media under reflux and ultrasound irradiation has been developed via a one-pot
multicomponent reaction, in which four new bonds were formed. Particularly valuable features of this
protocol including mild conditions, simple execution, broad substrate scope, and good yields of
products make it an efficient and promising synthetic strategy to build pyridine skeleton.
Keywords: Pyridines, sodium chloride, aqueous medium, salting effect, hydrophobic effect.
Introduction:
Nitrogen-containing heterocyclic compounds are widespread in nature, and their applications
in biologically active pharmaceuticals, agrochemicals, and functional materials are getting more and
more important1, densely substituted pyridine derivatives are one of the most important classes of
compounds owing to their widespread occurance as key structural subunits in numerous natural
products that exhibit many interesting biological activities2. In addition, these heterocyclic compounds
have found variety of applications in medicinal and pharmaceutical sciences. Particular pyridine
scaffold is core structure of a wide range of naturally occurring bioactive molecules, pharmaceuticals,
and functional materials3-5. Polysubstituted pyridine have also found to be antiprion6, antihepatitis B
virus7, antibacterial8, anticancer agents9 and as potassium channel openers for treatment of urinary
incontinence10. Moreover, some of the compounds were discovered to be highly selective ligands for
adenosine receptors11, which are recently recognized as potential targets for the development of new
drugs for the treatment of Parkinson’s disease, hypoxia/ischemia, asthma, kidney disease, epilepsy 12.
Multicomponent reactions (MCRs) have drawn interesting efforts owing to their exceptional
synthetic efficiency, intrinsic atom economy, high selectivity, and procedural simplicity13. MCRs are
useful for the expedient creation of chemical libraries of structurally related, medicinally significant
1

drug-like compounds14. Therefore, the design of new MCRs attracted great attention especially in the
areas of drug discovery and organic synthesis.
In most of the existing studies on 2-amino-3, 5-dicarbonitrile-6-thio pyridine derivatives, these
compounds have been synthesized following three-component condensation reaction of aldehydes,
malononitrile and thiophenol either in the presence of Lewis/Bronsted acids or bases15. Amongst the
various catalysts utilized for this purpose include DBU, DABCO, Et3N, piperidine, KF/alumina,
K2CO3/KMnO4, ZnCl2, Si & Mg nanoparticles, ionic liquids, Zn(II) or a Cd(II) metal–organic
framework etc. More importantly, most of these methods require the use of hazardous organic solvents
and some of them need harsh reaction conditions and many of them are either not eco-friendly or
cause environmental pollution. Consequently, there is still need to develop a more efficient, simple,
milder and high yield protocol for the synthesis of highly substituted pyridines.
During the last three decades ultrasound mediated reactions have emerged as efficient and
attractive methodologies in organic synthesis16. Compared with traditional methods, these reactions
are more convenient and advantageous. Thus, various organic reactions can be carried out under
ultrasound irradiation within shorter reaction time and mild conditions affording high yields of desired
products17.
Recently there has been increasing concern with regard to the tight legislation on the
maintainence of ‘greenness’ in the synthetic pathways and processes. Due to gr`owing environmental
concern, designing of straightforward and practical chemical syntheses of drugs and fine chemicals
that satisfy economic criteria is a major challenge18. The use of water is the preferred non-
conventional reaction medium in the design of green chemical syntheses19 and significant efforts has
been made in performing organic synthesis in aqueous medium20. The NaCl has emerged as a useful
catalyst for the construction of various carbon–carbon and carbon–heteroatom bonds. Several
advantages such as its excellent solubility in water, eco-friendly nature, easy handling, cost-
effectiveness, high reactivity, and easy work-up procedures made NaCl as an effective catalyst in
organic synthesis21.
Therefore, in an endeavor towards the development of greener synthetic protocols for the
synthesis of highly functionalized pyridine derivatives herein, we describe the one-pot three
component condensation of aryl aldehyde, malanonitrile and thiophenol using sodium chloride as an
additive in aqueous media under ultrasonic irradiation as well as at conventional technique, which
afford 2- amino-3, 5-dicarbonitrile-6-thio-pyridines in higher yields within shorter reaction times by
avoiding toxic catalysts and hazardous solvents.
2

Results and Discussion
In continuation of our research work on the synthesis of heterocyclic compounds22, we have
designed a unique synthetic route to privileged heterocyclic scaffolds of medicinal significance that
combine synthetic efficency of multicomponent protocols with the environmental benefit of using
water as a reaction medium.
Initially, in order to optimize the reaction conditions, we have choosen the reaction of
benzaldeyde (1a), malononitrile (2) and thiophenol (3) as a standard model reaction (Scheme 1). ) In
addition, ultrasound irradiation technique is successfully implemented to carry out the reactions.
Scheme 1. Standard model reaction
The effect of various catalysts on the model reaction was conducted (Table 1). The results
indicated that the catalyst had a significant effect on the product yield. According to literature, it has
15
become apparent that formation of pyridine does not take place in the absence of catalyst/additive
.
Neat reaction only leads to Knoevenagel condensation product of aldehyde and malononitrile. This
clarified the need of catalyst/additive for the formation of pyridine. In an order to evaluate the effect of
additives, various additives were used for performing the model reaction. Intentionally, chlorides of
the first group elements, i.e., Hydrochloric acid (HCl), Lithium Chloride (LiCl), Sodium Chloride
(NaCl), Potassium Chloride (KCl) and similar analogue of these salts viz. Ammonium Chloride
(NH4Cl) and some sodium halide NaBr and NaI were utilized for our purpose.
Our attempts started with the use of bronsted acid i.e., HCl (Table 1, entry 2) as an additive.
But, formation for the product was not observed during the reaction. However some Non acidic neutral
salts (metal chlorides) such as LiCl, KCl and acidic salt like NH4Cl (Table 1, entry 3-5) were used as
additive, however yields of the product in each case were found to be low to moderate. With this
results, some sodium halides such as NaBr and NaI and NaCl have been used for our further study and
it was observed that when we utilize some sodium halides reaction seems to proceed smoothly (Table
1, entry 6, 7). Surprisingly, when non-acidic salt, i.e. NaCl was used as an additive, the reaction was
completed in a shorter time with excellent yield of desired product.
3

Further, to know the precise role of a solvent, model reaction was performed under solvent free
condition at 100 °C. To our surprise, reaction in neat condition was observed to result with 55% yield
(Table 1, entry 13). Whereas, no product formation was observed in the absence of catalyst (Table 1,
entry 14). As the selection of an appropriate reaction medium is of crucial importance for the success
of the reaction the model reaction was screened by various solvents in the presence of NaCl under
conventional heating conditions and ultrasound irradiation. The results show that the effectiveness of
solvents on the product yield. The use of toluene, acetonitrile gave poor yields (Table 1, entries, 11,
12). Solvents like EtOH, MeOH and DMF gave moderate yields (Table 1, entries, 8-10). The best
conversion was observed when the reaction was performed in water (Table 1, entry 1) based on these
results, water was then selected as the medium for the further investigations. In order to establish the
appropriate quantity of water, the model reaction was investigated using 4, 6, 8, 10, and 12 mL of
water yielding desired product in 40%, 55%, 65%, 90% and 90% respectively (Table 1, entries, 15-
19). In these experiments, it was observed that 10 mL of water is sufficient to carry out the reaction
efficiently.
Table 1. Screening of the catalysts, solvents and amount of solventsa
Entry
1
Catalyst
NaCl
Solvent
Water
Water
Water
Water
Water
Water
Yieldb (%)
90
2
HCl
LiCl
NR
52
3
KCl
4
69
62
NH4Cl
NaBr
NaI
5
6
74
70
7
Water
Ethanol
NaCl
8
65
59
Methanol
DMF
9
NaCl
NaCl
10
11
12
13
14
15
16
17
18
19
62
Acetonitrile
Toluene
Neat*
40
36
NaCl
NaCl
NaCl
55
Water
NR
64
No Catalyst
NaCl
Water (4 mL)
Water (6 mL)
Water (8 mL)
Water (10 mL)
Water (12 mL)
69
78
NaCl
NaCl
NaCl
90
90
NaCl
aReaction conditions: 1a (1 mmol), 2 (2 mmol), 3 (1
mmol), Catalyst (15 mol%), in solvent (10 mL) at reflux
temp. for 2 h; *At neat condition reaction temp. was 100
°C; NR= No reaction;bIsolated yields.
4

In order to know the reaction condition, we have used the combination of NaCl and water to
model reaction at room temperature. It was noted that, the reaction leads to only Knoevenagel
condensation of an aldehyde and malononitrile, and trace amount of product formed, (Table 2, entry
1). Therefore, in an attempt to reduce reaction time and increase product yields, model reaction tested
at higher temperature. To evaluate the appropriate temperature we carried out the model reaction at
60°C, 80°C and reflux condition, (Table 2, Entries, 2, 3, 4) however increasing the temperature
enhances the reaction rate substantially with respective 45%, 62% and 90% yield.
To evaluate the appropriate concentration of the catalyst for the model reaction, we investigate
the model reaction at different concentration of NaCl such as 5, 10, 15 and 20 mol%. The product was
formed in 60, 72, 90 and 90% yield, respectively, (Table 2, Entries, 4-7). This shows that 15% of
NaCl is sufficient to carry out the reaction efficiently. With these satisfactory results in hand, it was
decided to use NaCl for further studies. To generalize the optimized reaction condition, some
substituted aldehydes were allowed to undergo this three-component reaction.
Table 2. Effect of the concentration of catalyst and temperaturea
Entry Temperature(°C) Catalyst (%) Yieldb (%)
1
2
3
4
5
6
7
R.T.
60
15
15
15
15
5
Trace
45
62
80
Reflux
Reflux
Reflux
Reflux
90
60
10
20
72
90
aReaction conditions: 1 (1 mmol), 2 (2 mmol), 3a (1
mmol), and NaCl (15 mol%) in water (10 mL) for 2 h;
bIsolated yields.
Selectivity of NaCl for catalysing this reaction is attributed to the salting effect. It is well
known that most of the organic molecules show dislike nature towards the water and hence in the
presence of water molecules organic substrates come much closer during the reaction due to the
hydrophobic effect. Ultimately hydrophobic effect enhances the concentration of organic substrate in
the reaction medium, thereby causing the more and more collisions of reacting species, which
generates the activation energy in the favour of product formation. This hydrophobic effect can be
increased by addition of NaCl in medium, specifically when reaction medium is aqueous due to the
salting out effect. When NaCl is added in water it dissociate into Na+ and Cl- ions. These ions
afterword get solveted by water molecules resulting in the less availability of water molecules for
interaction with organic molecules. Therefore, solute-solute interaction becomes stronger than solute-
5

solvent interaction, which is supported by volume contraction. Above discussed salting out effect of
NaCl is well understood in literature23. This salting out effect is more pronounced for NaCl than for
KCl24 which shows the advantage of NaCl as a catalyst. The reaction was proposed via the
Knoevenagel condensation of an aldehyde and malanonitrile, followed by the Michael addition of
second molecule of malanonitrile on the Knoevenagel product. This then reacts with thiophenol and
under goes air oxidation to afford final product (Figure 1).
R1
NC
H
H
CN
CN
S
R
R
H
H
CN
CN
C
O
-H2O
H
N
H
CN
R
NC
C
N
NH
H
R
N
R
R
H
NC
NC
H2N
CN
R1
NC
H2N
CN
R1
[O]
CN
R1
N
S
S
H2N
N
S
Figure 1: Possible mechanism for the synthesis of Highly Functionalized Pyridines.
6

Table 3. Synthesis of highly functionalized pyridines.a
Product
With USa
Without USb
M. P. (°C)d
Time
Time
R
Yieldc (%)
Yieldc (%)
(Min)
20
20
22
20
20
20
25
20
25
25
20
35
30
(hrs)
2
4a
4b
4c
4d
4e
4f
4-Cl
H
91
88
85
92
84
82
85
84
80
87
85
25
22
90
87
85
90
82
80
84
82
80
85
83
20
18
223-224 [15]
212-214 [15]
242-245 [15]
286-288 [15]
230-234 [15]
217-220 [15]
226-229 [15]
212-215 [15]
178-180 [15]
310-314 [15]
206-210 [15]
228-230 [15]
145-147 [15]
2
4-OMe
2
4-NO2
2
Piperonyl
4-OH-3-OMe
3,4-(OMe)2
2-Thienyl
2-Furyl
2
2
4g
4h
4i
2
2
2
4j
4-OH
2
4k
4l
4-Me
2
Acetaldehyde
3
4m
Propionaldehyde
3
aReaction conditions: 1a (1 mmol), 2 (2 mmol), 3 (1 mmol), Catalyst (15 mol%), in water (10 mL)
under ultra sonic waves. bReaction conditions: 1a (1 mmol), 2 (2 mmol), 3 (1 mmol), Catalyst (15
mol%), in solvent (10 mL) at reflux condition. cIsolated yield. dCompounds were characterized by 1H
NMR, MS spectral data and were compared with the reference compounds.15
In further set of experiment, model reaction has been performed using non-classical activation
energy source, that is, ultrasound irradiation. In this experiment, model reaction was found to proceed
effectively within very short reaction time delivering the desired product in excellent yield. Inspire by
this, it was decided to synthesize number of derivatives following developed reaction condition by
classical as well as non-classical method.
7

For assessing the generality of optimized reaction condition, wide range of substituted
aldehydes were allowed to undergo this three component condensation reaction. Aromatic aldehydes
with several functionalities were found to be compatible under the optimized reaction conditions.
Heteroaromatic aldehydes such as piperonal, thiophene-2-carbaldehyde and furfuraldehyde also
proved to be amenable under these reaction conditions. Unfortunately, aliphatic aldehydes such as
acetaldehyde and propionaldehyde afforded the desired product in lower yields. All the synthesized
compounds were charecterized by spectral data and compared (MS, NMR) with authentic sample. This
comparison revealed that the compounds synthesized by this newly developed method were exactly
similar in all aspects to the reference compounds15. The developed method is simple, efficient and
good contribution in field of pyridines.
Conclusion:
In conclusion, we have developed one pot multicomponent protocol for the synthesis of highly
functionalized pyridines using aldehydes, malononitrile and thiophenol in the presence of sodium
chloride as a readily available reaction accelerator. Utilization of NaCl in aqueous solvent system is
proved as a green reaction medium for carrying out organic transformations. Developed synthetic
method has several advantages such as wide scope of substrate, easily available catalyst, operational
simplicity, easy work up procedure and higher product yields.
Acknowledgements:
Authors are thankful to Dr. Babasaheb Ambedkar Marathwada University, Aurangabad for
providing laboratory facilities. One of the authors JBG is thankful to UGC, New Delhi, India for
financial assistance in the form of NET- Senior Research Fellowship.
8

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General experimental procedure for the synthesis of highly functionalized pyridines (4a-m):
Conventional method: To a mixture of aldehyde 1 (1 mmol) and malononitrile 2 (2 mmol) in
10 mL water, catalytic amount of sodium chloride (NaCl) (15 mol %) was added. After 10-15
minutes of stirring, solid was precipitated out indicating the rapid knoevenagel condensation.
To this reaction mass, thiophenol 3 (1 mmol) was added and reaction mass was refluxed for
time specified in Table 3, until the complete conversion of the starting materials was achieved.
Progress of the reactions was monitored with the help of TLC. After completion of the
reaction, thick reaction mass thus obtained was poured on crushed ice, stirred well and
collected by simple filtration, which was further washed with water (10 mL) followed by
aqueous ethanol (10 mL) to afford crude product 4. This crude product (4a) was purified by
recrystallization technique from 10% aqueous ethanol as a solvent.
Ultrasound method: To a mixture of aldehyde 1 (1 mmol) and malononitrile 2 (2 mmol) in 10
mL water, catalytic amount of sodium chloride (NaCl) (15 mol %) was added and it was
subjected to ultrasound irradiation for 3 min. After 3 minutes, thiophenol 3 (1 mmol) was
added and reaction mass was irradiated for time specified in Table 3, until the complete
conversion of the starting materials was achieved. Reaction progress was monitored by TLC
(ethyl acetate/n-hexane: 1:9). After completion of the reaction, thick reaction mass thus
obtained was poured on crushed ice, stirred well and collected by simple filtration, which was
10

further washed with water (10 mL) followed by aqueous ethanol (10 mL) to afford crude
product 4. This crude product (4a) was purified by recrystallization technique from 10%
aqueous ethanol as a solvent.
Spectral Data of Representative compound:
1
2-Amino-4-(4-chlorophenyl)-6-phenylsulfanylpyridine-3,5-dicarbo-nitrile (4a): H NMR (400
MHz, DMSO-d6): δ 7.46-7.49 (m, 3H, Ar-H), 7.57 (d, 2H, J = 8 Hz, Ar-H), 7.59 (d, 2H, J = 8
Hz, Ar-H), 7.64 (d, 2H, J = 8 Hz.) 7.82 (brs, 2H, -NH2); 13C NMR (50 MHz, CDCl3): δ 87.19,
93.32, 114.78, 115.19, 117.12, 125.38, 127.61, 128.92, 130.18, 130.43, 132.74, 135.29, 157.82,
159.61, 166.09; ES-MS: 361.2 (M-), 363.2 (M-+2).
11

Graphical Abstract
Sodium chloride: A proficient additive for the synthesis of pyridine derivatives
in aqueous medium.
Jitendra B. Gujar, Mahendra A. Chaudhari, Deepak S. Kawade and Murlidhar S. Shingare *
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad -
431004, Maharashtra, India.
In the present work, a facile and convenient synthesis of substituted pyridines has been
developed via a one-pot multicomponent reaction of easily available aromatic aldehydes,
malononitrile and thiophenol under aqueous media and in the presence of NaCl as mild
conditions. A series of functionalized pyridines were thus obtained by this multicomponent
reaction, in which four new bonds were formed. Particularly valuable features of this protocol
including mild conditions, simple execution, broad substrate scope, and good yields of products
make it an efficient and promising synthetic strategy to build pyridine skeleton
12