Ionic liquid promoted efficient three-component synthesis of 2-thioxo-2H-thiopyrans

Article abstract of DOI:10.1080/10426507.2011.601776

An efficient one-pot three-component method for the synthesis of a variety of 2-thioxo-2H-thiopyrans has been described. Fairly good yields are obtained by cyclization reactions of arylidenemalononitriles, derived in situ from ketones and malononitrile, w

Full text of DOI:10.1080/10426507.2011.601776

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Phosphorus, Sulfur, and Silicon and the
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Ionic Liquid Promoted Efficient Three-
Component Synthesis of 2-Thioxo-2H-
Thiopyrans
Abbas Ali Esmaeili a , Rahele Hosseinabadi a & Maryam Razi a
a Chemistry Department , University of Birjand , Birjand, Islamic
Republic of Iran
Published online: 31 Oct 2011.
To cite this article: Abbas Ali Esmaeili , Rahele Hosseinabadi & Maryam Razi (2011) Ionic Liquid
Promoted Efficient Three-Component Synthesis of 2-Thioxo-2H-Thiopyrans, Phosphorus, Sulfur, and
Silicon and the Related Elements, 186:12, 2267-2273, DOI: 10.1080/10426507.2011.601776
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Phosphorus, Sulfur, and Silicon, 186:2267–2273, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.601776
IONIC LIQUID PROMOTED EFFICIENT
THREE-COMPONENT SYNTHESIS OF
2-THIOXO-2H-THIOPYRANS
Abbas Ali Esmaeili, Rahele Hosseinabadi, and Maryam Razi
Chemistry Department, University of Birjand, Birjand, Islamic Republic of Iran
GRAPHICAL ABSTRACT
NH2
O
NC
CN
CN
[BMIM]Br, r.t.
EtONa, 2. h.
S
+
+ CS2
CH
R2
R1
S
R1
1
R2
2
Abstract An efficient one-pot three-component method for the synthesis of a variety of
2-thioxo-2H-thiopyrans has been described. Fairly good yields are obtained by cyclization
reactions of arylidenemalononitriles, derived in situ from ketones and malononitrile, with car-
bon disulfide in the presence of a base in the ionic liquid 1-butyl-3-methylimidazolium bromide
as reaction medium.
[Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
resource: Selected Data.]
Keywords Three-component reaction; malononitrile; 1-butyl-3-methylimidazolium bromide;
ionic liquids; 2-thioxo-2H-thiopyrans
INTRODUCTION
Multicomponent reactions (MCRs) have attracted increasing attention of synthetic
chemists as an effective method to generate molecular diversity.1–3 Devising such types
of MCRs, that achieve the formation of multiple bonds in a single operation in which
three or more reactants are combined together to generate a desired product without the
isolation of any intermediate, is one of the major challenges in modern organic synthesis.4,5
In contrast to the multistep syntheses, such approaches avoid time-consuming tasks and
costly purification processes, as well as protection–deprotection steps. Additionally, they
are inherently more environmentally benign and atom-economic,6 providing a powerful
Received 11 March 2011; accepted 26 June 2011.
We gratefully acknowledge financial support from the Research Council of the University of Birjand.
Address correspondence to Abbas Ali Esmaeili, Chemistry Department, University of Birjand, P.O. Box
97175/615, Birjand, Islamic Republic of Iran. E-mail: aa esmaeili@yahoo.com
2267

2268
A. A. ESMAEILI ET AL.
approach toward the one-pot synthesis of diverse and complex compounds as well as small
and drug-like heterocycles.7
Nowadays, there is a trend toward the least consumption of organic solvents due
to environmentally maligned chemical processes. In principle, the application of ionic
liquids, as environmentally benign solvents, has the potential to exhibit low human toxities
and ecotoxities.8,9 The most commonly used ionic liquids are based on imidazolium salts
including organic cation and appropriate anions. They currently receive a lot of attention as
solvent, because they have mp close or near to r.t. and also are immiscible with a range of
organic solvents meaning thereby that organic products can be removed and the ionic liquid
can be recycled.10 Due to the solvophobic properties, ionic liquids are capable of generating
an internal pressure and promote the association of the reactants in a solvent cavity during
the activation process and accelerate the reaction. This property of ionic liquids is very
effective concerning MCRs in which the entropy of reaction decreases in the transition
state.11–13
New approaches have been designed and developed to synthesize diverse arrays of
drugs which are increasingly in demand in medicinal chemistry. In this context, thiopy-
rans have attracted more attention because of their backbone similarity with pyran units
as useful biological properties.14 Particularly, 4-methyl-5-pyrazinyl-1,2-dithiole-3-thione,
(Oltipraz), is one of the most promising agents against environmentally induced hepato-
cellular carcinoma15 and other cancers.16 Also, 1,2-dithiole-3-thione itself protects against
neoplasia.17 In the meantime, several 5- and 6-membered sulfur heterocycles have been used
as hepatoprotective agent. Among the 6-membered sulfur heterocycles, 6-amino-4-aryl-2-
thioxo-2H-thiopyran-5-carbonitriles demonstrated activity in all the enzyme parameters at
an amount of 6 mg/kg dose (P. O. × 7 days).18
In 1966, Gewald19 synthesized 6-amino-4-aryl-2-thioxo-2H-thiopyran-5-carbon
itriles by the cyclization of arylidenemalononitriles with carbon disulfide in the presence
of triethylamine in DMF within 24 h. To the best of our knowledge, this is the only method
for the synthesis of these compounds that has been described in the literature. However,
this method suffers from low product yields, long reaction times (24 h), use of solvent, and
limited library of products.
In view of the emerging importance of ionic liquids as novel reaction media and
the pharmacological activity of the 2-thioxo-2H-thiopyrans, and in line with our research
work on the synthesis of heterocycles,20 herein we wish to report our preliminary results
on the preparation of 6-amino-4-aryl-2-thioxo-2H-thiopyran-5-carbonitriles by the three-
component reaction of aryl methyl ketone (1), malononitrile, and carbon disulfide in the
presence of a base by using the ionic liquid 1-butyl-3-methylimidazolium bromide as an
environmental friendly solvent and promoter (Table 1).
RESULTS AND DISCUSSION
In investigation of the reaction conditions, the reaction of 2-acetyl naphthalene,
malononitrile with carbon disulfide at ambient temperature in the presence of a base was
selected as a model reaction. As shown in Table 2, the solvent loading exhibits an obvious
influence on the reaction yield. The best result (66% yields) was obtained with 1.5 equivalent
of sodium ethoxide in 1-butyl-3-methylimidazolium bromide ([BMIM]Br) at r.t. (Table◦2,
Entry 8). Also, the reaction was carried out in various amounts of ionic liquid at 25 C
(Table 3). The optimum amount of [BMIM] bromide was 1.5 equivalent (Table 3, entry 3),
a higher amount of IL did not increase the yield noticeably.

EFFICIENT THREE-COMPONENT SYNTHESIS OF 2-THIOXO-2H-THIOPYRANS
2269
Table 1 Room temperature ionic liquid-promoted synthesis of 6-amino-2-thioxo-2H-thiopyrane-5-carbonitrile
derivatives (2a–i) in the presence of base
Entry
1
Ketone
Product
Yielda (%)
79
NH
2
O
NC
S
CH3
S
1a
2a
NH2
O
2
60
NC
CH3
S
OMe
S
1b
2b
OMe
NH2
O
3
4
68
65
NC
S
MeO
S
1c
OMe
2c
NH2
O
NC
NC
S
MeO
1d
S
2d
MeO
O
NH2
5
6
66
87
S
1e
S
2e
O
NH2
NC
S
1f
S
2f
O
NH2
7
8
9
65
65
80
NC
S
1g
S
2g
NH2
O
NC
O
S
O
S
1h
2h
NH2
O
NC
S
S
1i
2i
aIsolated yield.
Using the optimized reaction conditions, we proceeded to probe the effect of different
substrates in the formation of highly substituted 2-thioxo-2H-thiopyrans (Table 1). Not
only electron-rich aryl ketones, but also electron-deficient aryl ketones in the reactions
afforded 2-thioxo-2H-thiopyran derivatives in 60–87% yields (Table 1). The 2-thioxo-2H-
thiopyrans formed can be obtained in pure form by re-crystallizing or passing the crude
products through a short plug of silica.
Our protocol exhibits a “green” method for the synthesis of 2-thioxo-2H-thiopyran
derivatives involving C S bond using methyl ketones as the starting materials. Our proce-
dure introduces a simple, mild, and useful approach to a variety of 2-thioxo-2H-thiopyran
derivatives.

2270
A. A. ESMAEILI ET AL.
Table 2 Reaction of 2-acetylnaphthalene with malononitrile and carbon disulfide at ambient temperature under
various conditions
Entry
Solvent
CH3CN
DMF
DMSO
THF
Toluene
CH3NO2
CH2Cl2
[BMIM]Br
EtOH
Base (equiv.)
Yield (%)
Time
1
2
3
4
5
6
7
8
9
10
11
12
13
EtONa (1.5)
EtONa (1.5)
EtONa (1.5)
EtONa (1.5)
EtONa (1.5)
EtONa (1.5)
EtONa (1.5)
EtONa (1.5)
EtONa (1.5)
EtONa (1.5)
EtONa (1.5)
–
30
–
–
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
15
45
–
10
66
50
62
10
–
[BMIM] BF4
[BMIM] PF6
[BMIM]OH
[BzMIM]Cl
EtONa (1.5)
5
The structures of the products 2a–2i (Table 1) were deduced from the elemental
analyses, IR, 1H NMR, and 13C NMR spectra. The IR spectrum of 2a showed absorption
at 2200 cm−1 due to the CN triple bond, and two sharp bands at 3300 and 3250 cm−1 due
to asymmetric and symmetric vibrations of the NH2 group, and a C S absorption at 1260
1
cm−1, respectively. The H NMR spectrum of 2a exhibited a singlet readily recognized
as arising from CH-C S (δ = 6.7 ppm), and a singlet (δ = 7.5 ppm) due to aromatic
protons, along with a broad singlet for two amine protons (δ = 9.2 ppm). The 13C NMR
spectrum of 2a showed 10 distinct resonances in agreement with the suggested structure.
1
The H NMR and 13C NMR spectra of 2b–j are similar to those of 2a except for the
R1 and R2 groups, which exhibit characteristic signals with appropriate chemical shifts.
The thiocarbonyl resonance in the 13C NMR spectra of 2a appears at 193.2 ppm. So, this
observation confirms the structure of the products.
Mechanistically, the reaction can be interpreted as follows. The carbanion 3 generated
by the deprotonation of vinylmalononitrile by sodium ethoxide adds to carbon disulfide
in a tandem reaction, to furnish the carbodithiate anion 4. Then, the anion 4 attacks the
carbon center of the CN triple bond by an intramolecular nucleophilic addition to produce
the imine 5, which finally isomerizes to give highly substituted 2-thioxo-2H-thiopyrans 2
(Scheme 1).
Table 3 Optimization of the amount of ionic liquid for the synthesis of 3e
Entry
Ionic liquid (mmol)
Base (mol%)
Yield (%)
1
2
3
4
0.5
1
1.5
2
EtONa (150)
EtONa (150)
EtONa (150)
EtONa (150)
0
52
66
66

EFFICIENT THREE-COMPONENT SYNTHESIS OF 2-THIOXO-2H-THIOPYRANS
2271
NC
CN
O
CS2
CN
CN
EtONa
+
CH2R2
R1
[Bmim]Br, rt
R1
CH
R2
1
3
NH2
NH
S
N
S
NC
R1
NC
NC
R1
S
H
[ 1,5 ]
H
R1
S
S
S
R2
R2
R2
4
5
2
Scheme 1
CONCLUSIONS
We have developed a simple, convenient, and practical method for the synthesis of
2-thioxo-2H-thiopyrans possessing potential biological properties. These products synthe-
sized through a one-pot three-component reaction of ketones, malononitrile, and carbon
disulfide in the presence of sodium ethoxide using ionic liquids as an environmentally
friendly and novel promoter medium. The use of simple and ready available starting mate-
rials and good yields of products are the main advantages of our method.
EXPERIMENTAL
Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid
analyzer. Melting points were measured on an Electrothermal 9100 apparatus and were un-
corrected. IR spectra (KBr pellets, ν/cm−1) were measured on a Perkin-Elmer 783 infrared
spectrophotometer. NMR spectra were measured using a Bruker DRX-250 Avance spec-
trometer at 300.13 MHz (1H) and 75.47 MHz (13C), respectively. [BMIM]Br, [BMIM]BF4,
[BMIM]PF6, [BMIM]OH, and [BzMIM]Cl ionic liquids were prepared according to the
procedures reported in the literature.21–23
Other reagents wereobtainedfromMerck(Germany) and Fluka(Buchs, Switzerland),
and all materials were used without further purification.
General Procedure
In a typical experiment, to a round-bottomed flask charged with NaOEt (1.5 mmol) in
ionic liquid [BMIM]Br (1.5 mmol), 2-acetylnaphthalene (1.0 mmol), and malononitrile (1
mmol) were added under stirring. The mixture was stirred for 2 h at ambient temperature,
and then carbon disulfide (2 mmol) was added drop-wise and the reaction mixture stirred
for about 20 min. On completion of the reaction as indicated by TLC, water (10 mL) was
added. The reaction mixture was extracted with ethyl acetate (3 × 5 mL), and the combined
organic solvent was removed under reduced pressure. In the case of 2a, 2c, 2d, 2e, and 2i,
cold acetonitrile (5 mL) was added to the residues to produce the pure solid products. For
2b, 2f, 2g, and 2h, the resulting crude products were purified by column chromatography
on silica gel (100–200 mesh) using ethyl acetate/hexane (2:1) to get the pure products.

2272
A. A. ESMAEILI ET AL.
Selected Data
6-Amino-4-phenyl-2-thioxo-2H-thiopyran-5-carbonitrile
(2a). Orange
powder (0.19 g, 79%). Mp 268 ◦C (dec.). IR: 3250–3300 (NH2), 2200 (CN), 1650 (C C),
1260 (C S). 1H NMR (DMSO) δ 6.7 (s, 1H, CH-C S), 7.5 (s, 5H, Ph), 9.2 (s, 2H, NH2).
13C NMR (DMSO) δ 84.2 (C-CN), 115.7 (CN), 125.7 (C-C S), 127.8 (Co of phenyl),
128.6 (Cp of phenyl), 130.0 (Cm of phenyl), 138.0 (Ci of phenyl), 153.0 (C-Ar), 171.5
(C-NH2), 193.2 (C S) ppm. Anal. Calcd for C12H8N2S2: C, 58.99; H, 3.30; N, 11.47%.
Found: C, 57.8; H, 3.2; N, 11.6%.
6-Amino-4-(2-methoxyphenyl)-2-thioxo-2H-thiopyran-5-carbonitrile
(2b). Orange powder (0.16 g, 60%). Mp 194 ◦C (dec.). IR: 3350 (NH) 3250 (NH), 2200
1
(CN), 1620 (C C), 1250 (C S). H NMR (DMSO) δ 3.8 (s, 3H, OCH3), 6.6 (s, 1H,
CH-C S), 7.0 (t, 3JHH = 7.34 Hz, 1H), 7.1 (d, 2JHH = 8.2 Hz, 1H), 7.3 (d, 2JHH = 7.2 Hz,
1H), 7.5 (t, 3JHH = 7.7 Hz, 1H), 9.1 (s, 2H, NH2). 13C NMR (DMSO) δ 55.5 (OCH3), 86.4
(C-CN), 111.8 (Cm of phenyl), 115.7 (CN), 120.6 (C-C S), 125.9 (Cm of phenyl), 127.2
(Co of phenyl), 129.0 (Cp of phenyl), 131.2 (Ci of phenyl), 151.4 (C-Ar), 155.8 (C-OCH3),
170.2 (C-NH2), 192.8(C S) ppm. Anal. Calcd for C13H10N2OS2: C, 56.91; H, 3.67; N,
10.21%. Found: C, 57.9; H, 3.7; N, 10.3%.
6-Amino-4-(3-methoxyphenyl)-2-thioxo-2H-thiopyran-5-carbonitrile
◦
(2c). Orange powder (0.19 g, 68%). Mp 255 C (dec.). IR: 3300 (NH), 3225 (NH),
1
2200 (CN), 1620 (C C), 1270 (C S). H NMR (DMSO) δ 3.79 (s, 3H, OCH3), 6.6 (s,
3
1H, CH-C S), 7 (3H, CH of phenyl), 7.39 (t, JHH = 8 Hz, 1H), 9.1 (s, 2H NH2).13C
NMR (DMSO) δ 55.7 (OCH3), 85.6 (C-CN), 113.6 (Cp of phenyl), 116.1 (Co of phenyl),
116.7 (CN), 120.4 (Co of phenyl), 125.0 (C-C S), 130.3 (Cm of phenyl), 140.2 (Ci of
phenyl), 153.6 (C-Ar), 159.5 (C-OCH3), 171.3 (C-NH2), 192.5(C S) ppm. Anal. Calcd
for C13H10N2OS2: C, 56.91; H, 3.67; N, 10.21%. Found: C, 56.1; H, 3.6; N, 10.3%.
6-Amino-4-(4-methoxyphenyl)-2-thioxo-2H-thiopyran-5-carbonitrile
(2d). Orange powder (0.18 g, 65%). Mp 272 ◦C (dec.). IR: 3300 (NH), 3250 (NH), 2200
1
(CN), 1600 (C C), 1250 (C S). H NMR (DMSO) δ 3.8 (s, 3H, OCH3), 6.7 (s, 1H,
CH), 7.0 (m, 2H), 7.5 (m, 2H), 9.1 (s, 2H, NH2). 13C NMR (DMSO) δ 55.8 (OCH3), 84.9
(C-CN), 114.5 (Cm of phenyl), 116.7 (CN), 125.7 (C-C S), 130.1 (Co of phenyl), 130.6
(Ci of phenyl), 153.4 (C-Ar), 161.2 (C-NH2), 171.8 (C-OCH3), 192.4 (C S) ppm. Anal.
Calcd for C13H10N2OS2: C, 56.91; H, 3.67; N, 10.21%. Found: C, 55.9; H, 3.6; N, 10.3%.
Supplementary Data
Selected data for products 2e–2i are available. Supplementary data associated with
this article can be found in the online version.
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