Novel ZnCl2-catalyzed one-pot multicomponent synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines

Article abstract of DOI:10.1016/j.tetlet.2009.04.051

ZnCl₂-catalyzed one-pot multicomponent synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines under microwave heating and conventional heating is described.

Full text of DOI:10.1016/j.tetlet.2009.04.051

Tetrahedron Letters 50 (2009) 3897–3900
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Tetrahedron Letters
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Novel ZnCl2-catalyzed one-pot multicomponent synthesis of 2-amino-
3,5-dicarbonitrile-6-thio-pyridines
*
Madabhushi Sridhar , Beeram C. Ramanaiah, Chinthala Narsaiah, Bellam Mahesh, Mudam Kumaraswamy,
Kishore K. R. Mallu, Vishnu M. Ankathi, Pamulaparty Shanthan Rao
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
ZnCl2-catalyzed one-pot multicomponent synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines
under microwave heating and conventional heating is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 March 2009
Revised 13 April 2009
Accepted 15 April 2009
Available online 18 April 2009
Keywords:
2-Amino-3,5-dicarbonitrile-6-thio-
pyridines
Multicomponent reaction
Lewis acid catalysis
ZnCl2
Microwave reaction
Multicomponent reactions (MCRs) have drawn high efforts in
recent years owing to exceptional synthetic efficiency, intrinsic
atom economy, high selectivity, and procedural simplicity.1 These
reactions constitute a valuable approach for creation of large li-
braries of structurally related, drug-like compounds, thereby en-
abling lead identification and lead optimization in drug
a true sense, these represent environmentally
friendly processes by reducing the number of steps, energy con-
sumption, and waste production.
Compounds with 2-amino-3,5-dicarbonitrile-6-thio-pyridines
ring system exhibit diverse pharmacological activities and are use-
ful as anti-prion,3 anti-hepatitis B virus,4 anti-bacterial,5 and anti-
cancer6 agents and as potassium channel openers for treatment
of urinary incontinence.7 In addition, several of these compounds
were discovered to be highly selective ligands for adenosine recep-
tors,8 which were recently recognized as potential targets for the
development of new drugs for the treatment of Parkinson’s disease,
hypoxia/ischemia, asthma, kidney disease, epilepsy, and cancer.9
In most of the existing studies10 on 2-amino-3,5-dicarbonitrile-
6-thio-pyridine derivatives, these compounds were synthesized by
multistep methods.8a,b,10 Recently, Evodkimov et al.11 have devel-
oped a simple protocol for preparation of 2-amino-3,5-dicarboni-
a base catalyst such as DABCO or triethylamine. As the yields of
2-amino-3,5-dicarbonitrile-6-thio-pyridine derivatives obtained
by this method are poor (20–48%), a modification to this method
was reported recently by Ranu et al.12 using the basic ionic liquid
1-methyl-3-butylimidazolium hydroxide or [bmIm]OH, which
could serve as a base as well as a reaction medium. In all the re-
ported methods for preparation of 2-amino-3,5-dicarbonitrile-6-
thio-pyridines, reactions were conducted essentially under base
catalysis. Conversely, we discovered that Lewis acids are also effec-
tive catalysts and we report here the first observation of one-pot
multicomponent reaction of a variety of aldehydes 1a–i with mal-
ononitrile 2 and thiophenol 3 under ZnCl2 catalysis producing 2-
amino-3,5-dicarbonitrile-6-thio-pyridines 4a–i in moderate to
good yields (Scheme 1).
In our preliminary studies, we have investigated the multi-
component reaction of tolualdehyde 1a with malononitrile 2
and thiophenol 3, using a variety of Lewis acids such as ZnCl2,
AlCl3, FeCl3, I2, Cu(OTf)3, InCl3, and BF3ÁEt2O as catalysts, to ob-
tain the corresponding pyridine derivative 4a under conventional
and microwave heating conditions using ethanol as a solvent
(Table 1).
discovery.2 In
In this study, ZnCl2 was observed to be highly efficient produc-
ing 4a in 73 and 77% yields under conventional and microwave
heating conditions, respectively. We have also synthesized a vari-
ety of pyridine derivatives 4 using ZnCl2 as catalyst under the same
conditions using aliphatic, aryl, and heteroaryl aldehydes. The rep-
resentative results13 are given in Table 2.
trile-6-thio-pyridines by
a multicomponent reaction of an
aldehyde, malononitrile, and a thiol in one pot in the presence of
* Corresponding author. Tel.: +91 40 2719 1772; fax: +91 40 27160387.
E-mail address: smiict@gmail.com (M. Sridhar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.051

3898
M. Sridhar et al. / Tetrahedron Letters 50 (2009) 3897–3900
R
NC
CN
O
CN
CNH
ZnCl2, Ethanol
reflux or MW
2
PhSH
R
H
S
N
NH2
Ph
1a-i
R = alkyl, aryl
2
3
4a-i
45-73% (Conventional heating)
46-77% (Microwave heating)
Scheme 1.
Evodkimov et al.11 have reported formation of side products
such as 1,4-dihyropyridine derivatives and enaminonitrile in their
base-catalyzed multicomponent reaction. However, under Lewis
acid catalysis, formation of these products has not been observed.
The plausible mechanism for the formation of pyridines under Le-
wis acid catalysis is shown in Scheme 2.
In conclusion, the present work describes an efficient one-pot
multicomponent synthesis of 2-amino-3,5-dicarbonitrile-6-thio-
pyridines under microwave and conventional heating conditions
using ZnCl2 as catalyst. This work is the first application of Lewis
acid as catalyst in the preparation of these compounds.
Table 1
Lewis acid-catalyzed multicomponent reaction of tolualdehyde, thiophenol, and
malononitrile
S. No.
Catalyst
Microwave heating
Time (min) Yield (%)
Conventional heating
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
ZnCl2
AlCl3
FeCl3
2
5
5
5
5
5
5
5
77
20
17
15
30
—
2
73
7
12
12
12
12
12
12
12
—
—
15
—
—
—
I2
Cu(OTf)3
InCl3
BF3ÁEt2O
—
—
K10 clay
R
R
R
R
CN
NC
CN
NC
NC
CN
NC
PhSH
C
N
2, LA
C
N
PhS
PhS
N
H
N
PhS
N
H
NH
LA
NH
LA
LA
-LA
R
R
N
R
N
NC
CN
NH
NC
CN
NC
CN
(O)
PhS
N
H
PhS
NH2
PhS
NH2
Scheme 2.
Table 2
ZnCl2-catalyzed multicomponent synthesis of pyridines
Entry
R-CHO 1
Product 4
Conventional heating
Microwave heating
% Yielda (reaction time)
Melting point (oC)
% Yielda (reaction time)
Me
CHO
a
73 (2 h)
77 (2 min)
208–21111b
NC
CN
Me
PhS
N
NH2
Ph
NC
CN
b
PhCHO
65 (2 h)
65 (2 min)
216–21811b
PhS
N
NH2

M. Sridhar et al. / Tetrahedron Letters 50 (2009) 3897–3900
3899
Table 2 (continued)
Entry R-CHO 1
Product 4
Conventional heating
Microwave heating
Melting point (oC)
% Yielda (reaction time)
% Yielda (reaction time)
CHO
c
45 (2.5 h)
46 (3 min)
67 (2 min)
62 (3 min)
219–220
221–223
174–175
NC
CN
PhS
N
NH2
F
CHO
F
d
62 (2 h)
NC
CN
PhS
N
NH2
O
e
60 (2.5 h)
NC
CN
NH2
CHO
O
PhS
N
OMe
CHO
MeO
f
52 (2 h)
60 (2.5 h)
50 (2 h)
50 (2 h)
50 (2 min)
60 (3 min)
52 (2 min)
50 (3 min)
226–228
OMe
OMe
NC
CN
PhS
N
NH2
S
g
208–2103b
287–28911b
220–222
NC
CN
CHO
S
PhS
N
NH2
NO2
CHO
NO2
h
NC
CN
PhS
N
NH2
HN
CHO
i
NC
CN
N
H
PhS
N
NH2
a
Isolated yields. All products were characterized by NMR, IR, and mass spectral data.
Acknowledgments
References and notes
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as described above into
a 25-ml round-bottomed flask provided with a
condenser and the mixture was refluxed with 15 ml of ethanol for 2 h. The
reaction was kept open to air during reflux and the progress of the reaction was
monitored with TLC. After completion of the reaction, ethanol was removed
under reduced pressure and the reaction mixture was extracted with ethyl
acetate (3 Â 10 ml). The combined extract was washed with water (1 Â 5 ml)
and brine (1 Â 5 ml) and was dried over anhyd. MgSO4. The organic layer was
concentrated under reduced pressure and the crude product was purified by
column chromatography (silica gel 100–200 mesh, ethyl acetate/hexane = 1:7)
to obtain 4d (0.86 g, 62%). 1H NMR (CDCl3, 300 MHz): d 5.5 (s, 2H), 7.3–7.4 (m,
2H), 7.4–7.7 (m, 7H); 13C NMR (CDCl3, 75 MHz): d 90.0, 91.5, 127.0, 128.5,
129.0, 129.5, 130.0, 136.0, 141.3, 159.2, 160.0, 169.5; IR (KBr, cmÀ1):
m 34951,
3341, 2904, 2884, 2206, 1616, 1540, 1459, 1259, 1018, 755, 682; ESI MS (m/z,
%): 346 (M+, 55), 345 (60), 327 (10), 251 (15), 237 (20), 183 (25), 146 (20), 109
(80), 77 (65), 65 (100), 51 (98); exact mass observed for C19H11FN4S: 346.069
(calcd: 346.063).
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