One-step, three-component synthesis of highly substituted pyridines using silica nanoparticle as reusable catalyst

Article abstract of DOI:10.1016/j.tetlet.2009.09.137

One-step synthesis of 'privileged medicinal scaffolds', 2-amino-3,5-dicarbonitrile- 6-sulfanylpyridines, has been demonstrated via a multicomponent reaction of aldehydes, malononitrile, and thiols using silica nanoparticle (NP) as catalysts. The silica NP

Full text of DOI:10.1016/j.tetlet.2009.09.137

Tetrahedron Letters 50 (2009) 6959–6962
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-step, three-component synthesis of highly substituted pyridines using silica
nanoparticle as reusable catalyst
*
*
Subhash Banerjee , Grigoriy Sereda
University of South Dakota, Department of Chemistry, 414 E. Clark Street, Vermillion, SD 57069, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
One-step synthesis of ‘privileged medicinal scaffolds’, 2-amino-3,5-dicarbonitrile- 6-sulfanylpyridines,
has been demonstrated via a multicomponent reaction of aldehydes, malononitrile, and thiols using silica
nanoparticle (NP) as catalysts. The silica NP catalysts are very mild (nearly neutral in nature), effective,
environmentally benign, and retain most of their activities after being reused for three times.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 4 September 2009
Revised 22 September 2009
Accepted 23 September 2009
Available online 27 September 2009
Keywords:
2
-Amino-3,5-dicarbonitrile-6-
sulfanylpyridines
Multicomponent reaction
Silica nanoparticles
Catalysis
The synthesis of ‘privileged medicinal scaffolds’ is highly impor-
tant as these compounds often act as ligands for a number of func-
tionally and structurally diverse biological receptors, and
consequently, serve as a platform for developing pharmaceutical
agents for diverse applications.1 An example of a ‘privileged scaf-
fold’ is a substituted pyridine of general structures A–C (Fig. 1).
Among them, 2-amino-3,5-dicarbonitrile-6-sulfanylpyridines (i.e.,
pyridines A) exhibit various pharmacological activities and are
R
N
A X = SR'
B X = OR'
C X = NHR'
NC
H N
CN
X
2
R = alkyl, aryl
Figure 1. Substituted pyridines A–C.
2
3
4
useful as antihepatitis B virus, antiprion, antibacterial, and anti-
5
clo[2.2.2]octane (DABCO) as a catalyst; however, yields of the pyr-
idines were not satisfactory (20–48%) due to the formation of a
significant amount of a side product, enaminonitrile. A basic ionic
liquid 1-methyl-3-butylimidazolium hydroxide, ([bmIm]OH),9c
piperidine/microwave, and a Lewis acid, ZnCl
recently exploited to improve the yields of the pyridines A. All
cancer agents, and as potassium channel openers for treatment of
6
urinary incontinence. Moreover, some of these compounds were
found to be highly selective ligands for adenosine receptors, impli-
cated Parkinson’s disease, hypoxia/ischemia, asthma, kidney
9
d
9e
7
2
,
have been very
disease, and epilepsy.
These vast applications have inspired the development of a
9
8
these above-mentioned procedures involved either a strong base
number of methods for the preparation of pyridine derivatives;
such as triethylamine, piperidine, DABCO, or [bmIm]OH or a Lewis
acid as a catalyst. This catalyst is toxic and corrosive in nature.
Thus development of efficient protocol involving a very mild
however, literature studies reveal that most of the methods involve
multistep sequences and low isolated yields, use of toxic and
expensive catalysts, and lack generality. The synthesis of pyridines
A through multicomponent reaction (MCR) of aldehydes, malono-
nitrile, and thiols has recently attracted much attention owing to
excellent synthetic efficiency, intrinsic atom economy, high selec-
tivity, procedural simplicity, and environmental friendliness. This
strategy for the preparation of pyridines A was first reported by
(
nearly neutral in nature), effective, and environmentally benign
catalyst for the synthesis of highly substituted pyridines A would
significantly increase the availability of 2-amino-3,5-dicarboni-
trile-6-sulfanylpyridines for medicinal applications.
Recent reports indicate that in addition to extensive use as a
supporting matrix, mesoporous silica in its nanoparticulate exhib-
9
a,b
Evdokimov et al.
using triethylamine or 1,4-diazabicy-
1
0
its remarkable catalytic activity.
Native silica nanoparticles
(
average size 50–100 nm) efficiently catalyzed the anti-Markovni-
*
Corresponding authors. Fax: +1 605 677 6397 (S.B.).
E-mail addresses: subhash.banerjee@usd.edu (S. Banerjee), gsereda@usd.edu (G.
10a
kov addition of thiols to inactivated alkenes
addition of active methylene compounds to conjugated alkenes.
and bis-Michael
10b
Sereda).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.137

6
960
S. Banerjee, G. Sereda / Tetrahedron Letters 50 (2009) 6959–6962
Table 1
R
Optimization of reaction parameters for the synthesis of pyridines A
O
CN
+ R'SH
NC
CN
SR'
Silica NPs
+
2
OMe
Ethanol, Reflux
OMe
+ 2
R
H
CN
2
.5 - 6 h
CN
H N
N
2
R, R' = alkyl and aryl
+ PhSH
CN
NC
CN
6
0-85 %
CHO
Scheme 1. Synthesis of highly substituted pyridines.
H2N
N
SPh
Entry
Catalyst
Solvent/condition
Time (h)
Yield (%)
In this study, we report the use of nearly monodispersed 50 nm sil-
ica NPs as a catalyst for the synthesis of ‘privileged scaffolds’, 2-
amino-3,5-dicarbonitrile-6-sulfanylpyridines, through one-step,
three-component condensation of aldehydes, malononitrile, and
thiols (Scheme 1).
1
2
3
4
5
6
Silica NPs
Iron oxide NPs
None
Silica NPs
Silica NPs
Silica NPs
EtOH/reflux
EtOH/reflux
EtOH/reflux
EtOH/rt
Toluene/reflux
DMF/reflux
2.5
2.5
24
24
24
3
85
0
0
0
20
45
The silica NPs were synthesized by water in oil microemulsion
1
1
method and were found to be neutral in water (pH ꢀ 7.0). Briefly,
ammonium hydroxide was added to a stirred solution of Triton X-
ethanol for a particular time period, followed by cooling to room
temperature resulted in the precipitation of pyridines A.
To investigate the scope and general applicability of this proce-
dure, we have carried out the synthesis of pyridines A using differ-
ent aldehydes and thiols (Table 2). We have found that a series of
1
00, cyclohexane, and water, and stirred for 24 h at room temper-
ature. Methanol was added to the microemulsion, which was next
centrifuged for 15 min; the precipitate was subsequently washed
with methanol and water to remove the Triton X-100. The pre-
pared nanoparticles were characterized by transmission electron
microscopy (TEM) (Fig. 2) and utilized in the MCR for the synthesis
of pyridines A.
Initially, we have explored and optimized different reaction
parameters for the synthesis of pyridine derivatives using MCR of
anisaldehyde, malononitrile, and thiophenol (Table 1, entry 1) as
a model reaction. First, we found that the reaction outcome does
not significantly depend on the size of silica NPs. Thus, 150–
Table 2
Silica NP-catalyzed synthesis of substituted pyridines A
R
CN
SR'
O
CN
CN
Silica NPs
NC
+ 2
+ R'SH
R
H
2
00 nm NPs led to slightly lower yields (by ꢀ10%), comparing with
H N
N
2
their 50 nm counterparts, used in this study. We have observed
that 10 wt % of catalyst (with respect to 1 mmol of aldehyde) effi-
ciently catalyzed the reaction leading to 2-amino-5-cyano-4-(4-
methoxy-phenyl)-6-phenylsulfanylnicotinic acid in excellent yield
0
Yield (%)a
Entry
R
R SH
Time (h)
Ref.
9a
1
2
Me
C H
4 9
PhSH
PhSH
6
6
60
60
n
13
(
85%). The same reaction was not successful in the absence of the
9
a
3
4
PhSH
PhSH
3
70
74
catalyst, even after refluxing for 24 h in ethanol (Table 1, entry
3
organic solvents such as DMF, toluene, and tetrahydrofuran.
). The catalyst showed best activity in ethanol compared to other
1
0b
The
9c
9a
2.5
above-mentioned reaction proceeded marginally in toluene (Table
, entry 5). Surprisingly, iron oxide NPs were found to be inactive
Cl
Cl
1
SH
SH
in catalyzing this MCR for the synthesis of pyridines A (Table 1, en-
try 2). Briefly, in a general experimental procedure,12 refluxing of a
mixture of aldehyde, malononitrile, thiophenol, and silica NPs in
5
6
7
8
9
6
60
85
65
75
84
HO
9c
PhSH
2.5
6
MeO
MeO
Me
13
HO
9
9
c
c
PhSH
2.5
2.5
PhSH
PhSH
O N
2
9
9
9
a
c
a
10
11
12
3
3
3
71
73
77
HO
PhSH
Br
N
PhSH
a
1
Yield refers to those pure isolated products characterized by spectroscopic ( H
NMR, 13C NMR, and IR) data.
Figure 2. TEM image of silica NPs.

S. Banerjee, G. Sereda / Tetrahedron Letters 50 (2009) 6959–6962
6961
0
ꢁ
various substituted aromatic aldehydes produced 2-amino-3,5-
dicarbonitrile-6-sulfanylpyridines in good to excellent yields (60–
and facilitated the formation of R S nucleophiles. Participation
of two proximate silanol groups (one as a hydrogen bond donor
and another one as an acceptor) in the reaction mechanism also
seems to be plausible.
8
5%). Interestingly, silica NPs also efficiently catalyzed the synthe-
sis of pyridines A using aliphatic aldehydes (Table 2, entries 1 and
2
) and thiols (Table 2, entries 5 and 7), whereas other reported re-
In conclusion, we have demonstrated an efficient and general
procedure for the synthesis of 2-amino-3,5-dicarbonitrile-6-sulfa-
nylpyridines via multicomponent reaction of aldehydes, malono-
nitrile, and thiols using silica NPs as a very mild (nearly neutral
in nature), effective, environmentally benign, and reusable cata-
lyst. Surprisingly, this mild catalyst efficiently catalyzed the con-
densation of both aromatic and aliphatic aldehydes with thiols
and malononitrile leading to pyridines A in practical yields. More-
over, this observation demonstrated the efficacy of silica NPs in the
synthesis of ‘privileged medicinal scaffolds’ via multicomponent
reaction. These findings will stimulate further research on the
applications of silica nanoparticles in organic synthesis.
9
c,d
agents
were unsuccessful. However, aliphatic aldehydes or thi-
ols afforded relatively lower yields of pyridines. For comparison,
the most representative reported results for the synthesis of pyri-
dines A via MCR of aldehydes, malononitrile, and thiols using dif-
ferent reagents or catalysts are outlined in Table 3. The observed
significant improvement of yields of the pyridine derivatives for
the silica NPs catalyst compared to other catalysts brings up the
question of a possible reaction mechanism. We believe that the
presence of the reactive –OH groups on the surface of the silica
NPs plays the major role in its catalytic activity.
In accordance with the mechanism outlined by Evdokimov
et al.,9a the reaction proceeds through silica NP/base-catalyzed Mi-
chael addition of the second molecule of malononitrile to the
Knoevenagel adduct (2), and an aldehyde with first molecule of
malononitrile followed by thiolate addition to C„N of the adduct
and cyclization to dihydropyridine (3), which upon aromatization
and oxidation (air) under the reaction conditions leads to pyridine
A (Scheme 2).
Acknowledgment
This work was supported by the Director, Office of Science, Of-
fice of Biological & Environmental Research, Biological Systems Sci-
ence Division, of the U.S. Department of Energy under Contract No.
DE-FG02-08ER64624.
It may be speculated that the polar amphoteric surface hydroxyl
groups of the silica NPs facilitate the interaction of absorbed weak
acidic and basic components due to stabilization of the corre-
sponding transition states and intermediates by hydrogen bonding.
This interaction with the neighboring silanol groups of the catalyst
is shown in Scheme 2 for the first reaction step. These surface
References and notes
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[
bmIm]OH
Aryl
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Piperidine
Aryl or alkyl Aryl
Aryl or alkyl Aryl
Aryl or alkyl Aryl or alkyl 60–85
No
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ZnCl
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Silica NPsa
Yes
—
a
Reactions were carried out in ethanol at refluxing conditions.
Reactions were performed in microwave heating at 90 °C.
b
CN
NC
NC
H
H
O
OH
NC
NC
CN
CN
H
O
H
CN
CN
2
O
R
H
H
R
CN
R'SH
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R
O
H
R
H
O
2
R
OH
SR'
1
a
1b
R
R
NC
HN
CN
NC
CN
NC
CN
NC
2H
CN
-
H N
2
N
SR'
H N
2
N
H
SR'
N
SR'
N
N
A
3
Scheme 2. Plausible mechanism for the synthesis of pyridine A.

6
962
S. Banerjee, G. Sereda / Tetrahedron Letters 50 (2009) 6959–6962
4-(4-methoxy-phenyl)-6-phenylsulfanylnicotinic acid (Table 2, entry 6):
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A
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thiophenol (110 mg, 1 mmol), and silica NPs (14 mg, 10 wt % with respect to
anisaldehyde) was refluxed in ethanol (3 ml) for 2.5 h followed by cooling to
room temperature. The precipitate was suspended in ethanol (5 ml) and
centrifuged for 15 min to separate the silica NPs. The supernatant was
evaporated, and the crude solid was recrystallized from ethanol to provide
crystals of 2-amino-5-cyano-4-(4-methoxy-phenyl)-6-phenylsulfanylnicotinic
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13
acid (320 mg, 85%). The spectroscopic data (IR, H NMR, and C NMR) are in
good agreement with the reported values.9 This procedure was followed for
the synthesis of all the substituted pyridines listed in Table 2. The recovered
catalyst was washed with ethanol and reused for subsequent reactions.
13. Chang, L. C. W.; Kunzel, J.; Mulder-Krieger, T.; Spanjersberg, R. F.; Roerink, S. F.;
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c
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sulfanyl-pyridines: Representative example for the synthesis of 2-amino-5-cyano-