Ionic liquid catalyzed 4,6-disubstituted-3-cyano-2-pyridone synthesis under solvent-free conditions

Article abstract of DOI:10.1007/s10562-011-0700-5

A green protocol for the synthesis of 4,6-disubstituted-3-cyano-2-pyridones from cyanoacetamides and 1,3-dicarbonyl compounds or chalcones using guanidine based ionic liquid as catalyst has been developed. In solvent-free conditions at 30 °C, [TMG][Lac] (1,1,3,3-tetramethylguanidine lactate) was found to have the highest catalytic activity among the ionic liquids including [TMG][Ac] (1,1,3,3-tetramethylguanidine acetate), [TMG][Pr] (1,1,3,3-tetramethylguanidine propionate), [TMG][n-Bu] (1,1,3,3-tetramethylguanidine n-butyrate) and [TMG][TFA] (1,1,3,3-tetramethylguanidine trifluoroacetate). The catalyst was recovered and recycled several times without significant loss of catalytic activity. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-011-0700-5

Catal Lett (2011) 141:1693–1697
DOI 10.1007/s10562-011-0700-5
Ionic Liquid Catalyzed 4,6-Disubstituted-3-Cyano-2-Pyridone
Synthesis Under Solvent-Free Conditions
•
Sunil S. Chavan Mariam S. Degani
Received: 31 May 2011 / Accepted: 9 September 2011 / Published online: 24 September 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A green protocol for the synthesis of 4,6-dis-
ubstituted-3-cyano-2-pyridones from cyanoacetamides and
1,3-dicarbonyl compounds or chalcones using guanidine
based ionic liquid as catalyst has been developed. In solvent-
free conditions at 30 °C, [TMG][Lac] (1,1,3,3-tetramethyl-
guanidine lactate) was found to have the highest catalytic
activity among the ionic liquids including [TMG][Ac]
(1,1,3,3-tetramethylguanidine acetate), [TMG][Pr] (1,1,3,
3-tetramethylguanidine propionate), [TMG][n-Bu] (1,1,3,3-
tetramethylguanidine n-butyrate) and [TMG][TFA] (1,1,3,3-
tetramethylguanidine trifluoroacetate). The catalyst was
recovered and recycled several times without significant loss of
catalytic activity.
their potential to enhancereaction rate [1–3]. Moreover, their
hydrophilicity or hydrophobicity and solvent miscibility can
be tuned by selecting the appropriate cation and anion [4, 5],
which renders them useful for facilitating catalyst recovery
from reaction mixtures.
Functionalized 2-pyridones have been reported to pos-
sess various pharmacological activities such as anticon-
vulsant [6], sedative [7], anti-atherosclerotic [8], anticancer
[9] and phosphodiesterase inhibition [9]. Substituted
3-cyano-2-pyridones are important intermediates in the
photo and dye industries [10] as well as for the synthesis of
vitamins [11]. They are also used as starting materials for
the synthesis of a number of fused heterocycles of bio-
logical importance such as isoxazolopyridines, pyrazolo-
pyridines, thienopyridines and pyridoquinazolines [12].
3-Cyano-2-pyridones can be synthesized by reaction of
cyanoacetamides with 1,3-diketones [13–15], acrylonitrile
[16, 17] or a,b-unsaturated carbonyl compounds [18] in
presence of various basic catalysts. Some studies have been
published on synthesis of 3-cyano-2-pyridones using
microwave irradiation in presence of strongly basic cata-
lysts [19, 20]. Most of these methods have one or more
limitations such as prolonged reaction time [12], harsh
refluxing temperatures which leads to more energy con-
sumption [15, 20], use of environmentally hazardous base
such as pyridine and piperidine [12, 15], use of volatile
organic solvents [14, 15], low product yields [18–20],
require acid–base work up and difficult or no recovery of
catalysts [12–15, 18–20].
Keywords 3-Cyano-2-pyridone Á Ionic liquid Á
Cyanoacetamides Á Acetyl acetone Á Guanidine Á
Solvent-free
1 Introduction
Today, ionic liquids (ILs) are extensively used as reaction
media as well as catalyst for organic transformations, due to
their physicochemical properties such as negligible vapor
pressure, excellent chemical and thermal stability, good
solvating ability, ease of recyclability, non-flammability and
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-011-0700-5) contains supplementary
material, which is available to authorized users.
In the quest of developing mild, simple, environmentally
friendly and solvent-free synthetic protocols, previously we
have reported several reactions including hetero-Michael
reaction [21], Knoevenagel condensation [22], Biginelli
reaction [23] and Heck reaction [24] using ILs as recy-
clable catalytic system. As new generation ILs, a wide
S. S. Chavan Á M. S. Degani (&)
Department of Pharmaceutical Sciences & Technology,
Institute of Chemical Technology, N. P. Marg, Matunga,
Mumbai 400 019, India
e-mail: ms.degani@ictmumbai.edu.in; m_degani@yahoo.com
123

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S. S. Chavan, M. S. Degani
were obtained with micromass-Q—Tof (YA105) spec-
trometer. TLC was run on silica gel coated aluminium
sheets (silica gel 60 F254, E. Merck, Germany) and visu-
alized in UV light at 254 nm.
2.2 General Procedure for 4,6-Dimethyl-2-Oxo-1,
2-Dihydropyridine-3-Carbonitrile in Catalyst GIL 1
Scheme 1 GIL 1 catalyzed reaction of cyanoacetamides with acetyl
acetone
In a typical experiment, cyanoacetamide (3.5 mmol),
acetyl acetone (3.5 mmol) and catalyst GIL 1 (1.4 mmol)
were charged into a 50 mL round-bottom flask with a
magnetic stirring bar. The reaction mixture was stirred at
30 °C for 60 min as mentioned in Table 1 during which
time a white solid precipitated. The progress of the reaction
was monitored by TLC. After the completion of reaction,
the reaction mixture was extracted thrice with hexane–
ethyl acetate mixture [(1:2 v/v) 3 mL] and passed over
anhydrous sodium sulphate. Evaporating the solvent under
reduced pressure gave the product. The recovered ionic
liquid was kept under vacuum for 2 h to remove volatiles
and stored in a desiccator for its reuse in subsequent cat-
alytic runs. The desired pure products were characterized
by comparison of their physical and spectral data with
those of known compounds [15, 18–20].
Scheme 2 GIL 1 catalyzed reaction of cyanoacetamide with
chalcones
range of guanidine ionic liquids (GILs) have been syn-
thesized and used as solvent as well as catalyst in the Henry
reaction, aldol reaction, Heck reaction and for the synthesis
of polysubstituted benzene [25–30].
In continuation of our endeavour in green synthesis and
using ILs as a recyclable and ecofriendly catalytic media,
herein, we report for the first time, a facile protocol for the
synthesis of 3-cyano-2-pyridones not only from cyanoac-
etamides and 1,3-dicarbonyl compounds (Scheme 1) but
also from cyanoacetamide and chalcones (Scheme 2) using
1,1,3,3-tetramethylguanidine lactate [TMG][Lac] (GIL 1)
as an efficient and recyclable catalyst at 30 °C, which is
superior to previous base catalyzed thermal methods and
overcomes the problems encountered with them.
3 Results and Discussion
A series of GILs such as 1,1,3,3-tetramethylguanidine lactate
[TMG][Lac], 1,1,3,3-tetramethylguanidine acetate [TMG][Ac],
1,1,3,3-tetramethylguanidine propionate [TMG][Pr], 1,1,
3,3-tetramethylguanidine n-butyrate [TMG][n-Bu] and
1,1,3,3-tetramethylguanidine trifluoroacetate [TMG][TFA]
were synthesized from 1,1,3,3-tetramethylguanidine and
organic acids with varied chemical structures as shown in
Table 1. We selected GIL-1 as a catalyst to investigate the
optimum reaction condition for the reaction between cya-
noacetamide and acetyl acetone at 30 °C as it has low vis-
cosity and more basicity than the other GILs. The effect of
the varying concentration of catalyst on the yield of product
and time required for the completion of reaction at 30 °C was
explored as shown in Table 2. It was observed that 0.4
equivalents of catalyst GIL 1 and reaction time of 60 min
gave optimum yield (Table 2, entry 6) at 30 °C.
The reactions of cyanoacetamide and acetyl acetone in
different GILs were also examined. It was observed that the
reactions of cyanoacetamide with acetyl acetone proceeded
slowly in GIL-2–4, with low to moderate yields even
after prolonged reaction time (Table 1, entries 2–4) and in
GIL-5 no reaction occurred (Table 1, entry 5). The above
results suggest that the chemical structures of GILs,
including both the anion and cation parts, played a crucial
role in product formation. From the data listed in Table 1,
2 Experimental
2.1 General Information
The ILs were prepared by previously reported method
without any modifications and characterized by FTIR and
1H NMR spectroscopy [31]. The reagents and solvents
were commercially available. Cyanoacetamide is com-
mercially available (Spectrochem Pvt. Ltd.). All synthe-
sized compounds were identified by spectroscopic data.
FTIR spectra were obtained on a Perkin-Elmer infrared
spectrometer with KBr discs and vmax was expressed as
1
cm-1. H-NMR and 13C-NMR spectra were recorded in
CDCl3 or DMSO-D6 on a JEOL AL 300 (300 MHz)
spectrometer with TMS as internal standard and the
chemical shifts were expressed in ppm. Mass spectral data
123

Ionic Liquid Catalyzed 4,6-Disubstituted-3-Cyano-2-Pyridone
1695
Table 1 : Reactions of cyanoacetamide with acetyl acetone in different GILs
Entry
1
GIL
Cation
Anion
pHa
Time (min.)
60
Yieldb (%)
93
GIL 1
10.93
2
3
4
5
a
GIL 2
GIL 3
GIL 4
GIL 5
CH3COO-
8.15
8.36
8.28
5.17
180
180
180
360
62
67
64
CF3COO-
NRc
Measured with 0.1 M aqueous solution of GIL [30]
Yield of isolated product
b
c
No reaction
with acetyl acetone to give the products in moderate to high
yields. It was also observed that the electronic nature of
substituents on the aromatic ring has some impact on the rate
of reaction. Substrates with electron donating groups are
comparatively less reactive than the substrates with electron
withdrawing groups on the aromatic ring and yields obtained
with substrates having electron donating groups were
slightly lower than substrates having electron withdrawing
groups on aromatic ring.
Table 2 Effect of varying concentration of catalyst GIL 1 on the
yields of product
Entry
GIL-1 (equi)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
–
120
40
NR
42
64
80
88
93
93
94
94
0.10
0.20
0.30
0.40
0.40
0.40
0.60
0.80
40
GIL-1 can be applied as an efficient catalyst not only for
the synthesis of 3-cyano-2-pyridones from 1,3-dicarbonyl
compounds and cyanoacetamide but also from chalcones
and cyanoacetamide (Scheme 2). We have used differ-
ent chalcones and cycanoacetamide for the synthesis of
3-cyano-2-pyridone derivatives under these reaction
conditions.
40
40
60
120
120
150
The recycling performance of catalyst GIL 1 in the same
model reaction was also explored. Isolation of product was
easier and did not need aqueous work up. Extraction of
product with a mixture of suitable solvent under efficient
stirring and then recovery of solvent under reduced pres-
sure gave the product. The catalyst was recovered by
washing repeatedly with mixture of hexane–ethyl acetate
and reused for several times without significant loss of
catalytic activity. The reusability of catalyst was quantified
by performing a set of experiments (Fig. 1). The catalyst
was recovered and reused three times without addition of
extra ionic liquid.
Reaction conditions: Cyanoacetamide (1 equi), acetyl acetone (1 equi)
and catalyst GIL-1, at 30 °C
a
Yield of isolated product
it seems that the GIL 1 is more basic may be due to
reduction in acidity because of intramolecular hydrogen
bonding in lactic acid. In addition, low viscosity [30] of
GIL 1 could also have a positive impact.
To explore the general validity of this process, a series of
4, 6-disubstituted-3-cyano-2-pyridones were prepared under
the optimized reaction conditions. Various types of aliphatic
and aromatic cyanoacetamides can be successfully reacted
123

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S. S. Chavan, M. S. Degani
The proposed reaction mechanism for GIL 1 catalyzed
also superior to earlier reported methods [18–20] for
3-cyano-2-pyridones (Table 3).
synthesis of 4,6-disubstituted-3-cyano-2-pyridones is shown
in Scheme 3. GIL abstracts the proton from cyanoacetamide.
This facilitates the nucleophilic attack of cyanoacetamide on
electrophilic carbon of 1,3-dicarbonyl compounds and sub-
sequent dehydration leads to the product formation.
4 Conclusions
GIL 1 can be used as an efficient and recyclable catalyst
for the synthesis of 3-cyano-2-pyridones not only from
cyanoacetamides and dicarbonyl compounds but also from
cyanoacetamide and chalcones and in most cases it was
We have developed a simple, mild and efficient protocol
for the synthesis of 4,6-disubstituted-3-cyano-2-pyridones
from cyanoacetamides and 1,3-dicarbonyl compounds or
chalcones at 30 °C using economical and environmentally
friendly [TMG][Lac] or GIL 1 as a recyclable catalyst.
Most importantly, the catalytic system is very easy to
prepare, handle and can be recycled and reused without
significant loss of catalytic activity. This method also offers
marked improvements with regard to operational simplic-
ity, ease of isolation, high isolated yields of products,
greenness of the procedure, no need of aqueous work up,
avoiding toxic catalysts and hazardous organic solvents.
Acknowledgment The financial support from UGC (SAP), Govt. of
India, is acknowledged by the author Sunil S. Chavan.
Fig. 1 Recyclability performance of IL
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