An efficient solvent-tuning approach for the rapid synthesis of thiazolidinone derivatives and the selective synthesis of 2-amino-4H-1,3-thiazin-4-one and dimethyl 3,3′-thiodiacrylates

Article abstract of DOI:10.1016/j.tetlet.2014.08.032

Green synthetic approach has been developed for the rapid generation of thiazolidinone derivatives as crystallized products under catalyst-free conditions in water by polarity adjustment with ethyl lactate as a co-solvent in excellent yields. Additionally

Full text of DOI:10.1016/j.tetlet.2014.08.032

Accepted Manuscript
An efficient solvent-tuning approach for the rapid synthesis of thiazolidinone
derivatives and the selective synthesis of 2-amino-4H-1,3-thiazin-4-one and di-
methyl 3,3’-thiodiacrylates
Garima Choudhary, Rama Krishna Peddinti
PII:
S0040-4039(14)01353-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.032
TETL 44999
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 April 2014
8 August 2014
9 August 2014
Please cite this article as: Choudhary, G., Peddinti, R.K., An efficient solvent-tuning approach for the rapid synthesis
of thiazolidinone derivatives and the selective synthesis of 2-amino-4H-1,3-thiazin-4-one and dimethyl 3,3’-
thiodiacrylates, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.08.032
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An efficient solvent-tuning approach for the rapid
synthesis of thiazolidinone derivatives and the selective
synthesis of 2-amino-4H-1,3-thiazin-4-one and
dimethyl 3,3’-thiodiacrylates
Leave this area blank for abstract info.
Garima Choudhary, Rama Krishna Peddinti*
R1
O
O
S
H2N
N
OR
S
OR
S
H2O
H2O:EL
R1
R1
N
N
O
O
N
N
H
H
R1
OR
OR
O
RO
RO
O
R1 = H
O
O
R = Me, Et
EL : Ethyl lactate

Tetrahedron Letters
1
Tetrahedron Letters
journal homepage: www. elsevier. com
An efficient solvent-tuning approach for the rapid synthesis of thiazolidinone
derivatives and the selective synthesis of 2-amino-4H-1,3-thiazin-4-one and
dimethyl 3,3’-thiodiacrylates†
Garima Choudhary, Rama Krishna Peddinti*
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee-247 667, Uttarakhand, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Green synthetic approach has been developed for the rapid generation of thiazolidinone
derivatives as crystallized products under catalyst-free conditions in water by polarity
adjustment with ethyl lactate as a co-solvent in excellent yields. Additionally, the interesting
findings on the selective synthesis of 2-amino-4H-1,3-thiazin-4-one and dimethyl 3,3’-
thiodiacrylates has been reported.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Catalyst-free
Solvent Tuning
Ethyl Lactate
Thiazolidinone
1,3-Thiazinone
In view of the increasing demands to develop and implement
environmentally benign protocols, Chemistry professionals are
on a continuous pursuit to generate ways to reduce or eradicate
the risks associated with chemical processes.1 Organic solvents
which comprise of alcohols, ethers, and petroleum-based solvents
such as halogenated hydrocarbons and toluene are used in most
of the organic transformations. Together with their high volatility
and poor toxicological and environmental profiles, the choice of
solvents, that can cut the environmental impact of the process
without losing their effectiveness, has become one of the major
concerns for organic chemists.2
Water, in terms of safety, cost and availability is one of the
greener solvents one can think of.3 However, due to the low
solubility of majority of organic compounds in water, its use as a
solvent is limited to some extent. Therefore there is a great need
for a benign and renewable alternative solvents4 those can be
tuned with water to generate different polarity conditions to
circumvent the solubility problem. Amid the alternative solvents
with sufficient properties, the most promising one is ethyl lactate,
a monobasic ester, which has remarkable solubility in both water
and non polar solvents as well.5 It is a safe and biodegradable and
has negligible
Thiazolidines represent a significant group of compounds
among nitrogen and sulphur containing heterocycles that cover
the mainstream of pharmacologically active molecules and
natural products.6 Thiazole moiety is an integral part of a number
of potent pharmaceutical agents such as cefotaxime. The broad
spectrum of antibiotics7 – ceftazidime, aztreonam, cefmenoxime,
cefotiam and ceftriaxone possessing thiazone subunit – are used
for the treatment of chronic bronchitis, pneumonia, pelvic
inflammatory disease, gonorrhoea, infections of the urinary tract,
Lyme disease, typhoid fever chlamydia infection and, meningitis.
Nitazoxanide, under the brand names alinia and annita is used for
the treatment of cryptosporidiosis in AIDS and chronic hepatitis
B. Moreover, meloxicam, a nonsteroidal anti-inflammatory drug
and anticancer drugs like tiazofurin and blenoxane also hold
thiazole skeleton in their structure. In addition some derivatives
of thiazolidine display potential anti-HIV activity. 6c,d
The
condensation
of
thioureas
with
dialkyl
acetylenedicarboxylates was reported to provide products of
either
six-membered
thiazinones8
or
five-membered
thiazolidinones.9,10 The ambiguity in the structure was later
resolved in favour of five-membered thiazolidinone by single
crystal X-ray analysis. 11
detrimental effect on air quality. Moreover, ethyl lactate is also
used in pharmaceutical preparation and fragrances, and in food
products.
Most of these reports are confined to limited examples. All the
above mentioned procedures have described the use of organic
solvents such as methanol,12a,b acetonitrile,12c and acetone12d as
———
* Corresponding author.Tel.: +91 133 228 5438; fax: +91 133 227 3560.
e-mail: rkpedfcy@iitr.ernet.in, ramakpeddinti@gmail.com;

2
Tetrahedron Letters
reaction media and almost all methods require refluxing
(Entries 11, 12, 16 and 18, Table 1) where the solid did not
separate out, the viscous reaction mixture obtained by decanting
the solvent was subjected to silica gel column chromatography.15
conditions with longer reaction times. Microwave-mediated
synthesis of thiazolidinones was also reported.13
The eminence and popularity of this pharmacologically
promising thiazole moiety prompted us to generate a highly
valuable protocol, which expedite their preparation. Therefore
based on our growing endeavors in investigating novel and eco-
friendly green synthetic protocols,14 we have developed an
alternative route for the generation of thiazolidinones by tuning
water with ethyl lactate (l-form) as a co-solvent. As a result of
this, different polarity conditions were developed which are
responsible for direct separation of final product from the
reaction mixture of thiourea derivative and dialkyl
acetylenedicarboxylate. Herein we report our preliminary results
on the synthesis of thiazolidinones using solvent tuning protocol.
S
S
S
H2N
NH2
N
N
N
N
H
H
H
H
1a
1c
1b
H3CO
OCH3
S
S
S
N
N
N
N
H
N
N
H
H
H
H
H
1f
1d
1e
At the outset, we performed the reaction using equimolar
quantities of thiourea and dimethyl acetylenedicarboxylate
(DMAD) in water at room temperature. Surprisingly within 3
minutes of stirring a white solid was separated out form the
reaction mixture in 99% yield which was confirmed as methyl 2-
S
S
N
N
N
N
H
H
H
H
1g
1h
S
S
1
(2-amino-4-oxothiazol-5(4H)-ylidene)acetate (2a) by H and 13C
N
N
N
N
H
H
H
H
NMR spectroscopic analysis. The reaction was then studied
between the thiourea derivatives 1b, 1e, 1j and DMAD in water
but in all these cases due to the solubility problem of thiourea
derivatives in water, the reactions proceeded slowly and took
longer time (up to 8 h) for the completion and required further
purification steps. Therefore, there is a great requirement for an
alternative green solvent which can be co-tuned with water to
overcome the solubility problem associated with thiourea
derivatives in water and to reduce the reaction times.
Captivated by the solvent tuning technique using
environmentally benign solvents, a reaction was investigated
with phenylthiourea (1b, 1 mmol) and DMAD (1 mmol) in 2 mL
of 40:60 composition of water and ethyl lactate (EL) to test its
effectiveness in the generation of thiazolidinones and
dramatically the solid product 3a separated out from the reaction
mixture in 5 min of stirring in 95% yield. These results inspired
us to expand our research towards the reaction of DMAD and
DEAD with thioureas 1a-1j bearing a variety of substituents
(Scheme 1 and Figure 1).
1i
1j
Figure 1. Structures of thiourea (1a) and its derivatives 1b-1j
As the conversion of the reactions of bis-benzyl thiourea 1j with
dialkyl acetylenedicarboxylates was not complete at room
temperature, these reactions were carried out on a pre-heated oil
bath at 50 oC (Entries 19 and 20). Upon lowering the temperature
of the reaction mixture, crystals of thiazolidinone derivatives
11a,b were obtained in near quantitative yields.
The assigned structures of the products are based on their
spectroscopic data. The structure of thiazolidinone 11b was
further confirmed from its XRD data (see supporting information
for ORTEP plot).16
Akin to thiazolidines, compounds comprising 4H-1,3-thiazine
core in their structure are found to exhibit potent pharmacological
and biological activity and are important synthetic intermediates
in organic transformations. Moreover, recent research has
established that 1,3-thiazine skeleton acts as BACE 2 inhibitors
for the treatment of diabetes.17 Due to their immense
pharmacological and biological action, researchers have
developed profound interest in their synthetic study.18-21
Encouraged by the results obtained from the reaction of thioureas
with DMAD/DEAD and the importance of 4H-1,3-thiazine core,
we then turned our attention towards the reaction of thiourea and
alkyl propiolate. As a prelude to this objective we performed a
reaction between thiourea (1a) and methyl propiolate. Thus,
methyl propiolate (2 mmol) was added to a stirred solution of
thiourea (1 mmol) in water (3 mL) at room temperature. The
solution became turbid immediately and a white fiber like solid
fairly soluble in chloroform started separating out and the
reaction was completed in 15 minutes with 89% yield.22 The
NMR spectroscopic analysis confirmed the product as the
OR'
OR'
O
O
COOR'
S
water
water:EL
S
S
R
R
N
N
R
rt
rt
H
H
H2N
O
N
O
N
N
R
R = alkyl, aryl
R = H
COOR'
a: R' = Me
b: R' = Et
2a,b
1
3a,b-11a,b
Scheme 1. Synthesis of thiazolidinones from variously substituted
thioureas with dialkyl acetylenedicarboxylates
The reaction of N,N’-diarylthioureas 1c-e bearing mono methyl
or dimethyl substituents on the aromatic residue proceeded
cleanly with DMAD/DEAD in 50:50 composition of water and
ethyl lactate to afford the corresponding solid products 4a,b-6a,b
in excellent yields (Table 1). The reaction of thioureas 1f-j
having other aryl or alkyl substitutions were also performed in
varying composition of water and ethyl lactate. In the cases

Tetrahedron Letters
3
Table 1. Synthesis of thiazolidinones in water tuned with ethyl lactate as a co-solvent at room temperature.
OR'
OR'
O
O
COOR'
S
water
water:EL
S
S
R
R
N
N
R
rt
rt
H
H
H2N
O
N
O
N
N
R
R = alkyl, aryl
R = H
COOR'
a: R' = Me
b: R' = Et
2a,b
1
3a,b-11a,b
Thiourea/derivative
Dialkyl acetylene-
dicarboxylate (R’)
Reaction time
(min)
Solvent composition
(Water:EL)
Yielda,b
(%)
Entry
Product
R
1
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
H
Me
Et
3
3
6
6
5
5
5
5
100:0
100:0
40:60
40:60
50:50
50:50
50:50
50:50
2a
2b
3a
3b
4a
4b
5a
5b
100
100
95
H
Ph
Me
Et
Ph
94
C6H4-m-Me
C6H4-m-Me
C6H4-p-Me
C6H4-p-Me
Me
Et
95
95
Me
Et
97
95
C6H3-m,m’-
dimethyl
C6H3-m,m’-
dimethyl
9
Me
Et
4
4
50:50
50:50
96
1e
1e
6a
6b
10
94
11
12
13
14
15
16
17
18
19
20
1f
1f
1g
1g
1h
1h
1i
C6H4-p-OMe
C6H4-p-OMe
α-naphthyl
α-naphthyl
cyclohexyl
cyclohexyl
n-propyl
Me
Et
6
6
5
5
3
4
4
4
6
6
30:70
30:70
40:60
40:60
60:40
60:40
60:40
60:40
20:80
20:80
7a
7b
91c
93c
96
Me
Et
8a
8b
94
Me
Et
97
9a
93c
9b
Me
Et
10a
10b
11a
11b
97
n-propyl
94c
97d
98d
1i
benzyl
Me
Et
1j
1j
benzyl
b
aOf pure products. The crystallized product obtained from the reaction mixture was filtered and washed with water to afford analytically pure products 2a-
6b, 8a,b, 9a and 10a, unless otherwise mentioned. cThe viscous liquid obtained from the reaction was subjected to column chromatography. dReaction was
carried out at 50 oC (pre-heated oil bath) and the crystallized product was filtered and washed with water.
mixture of cis,cis-, cis,trans- and trans,trans-isomers of dimethyl
3,3’-thiodiacrylate (12a, 12b and 12c, Scheme 2). Later, for the
as methanol, ethyl lactate. The assigned structure of 13 is based
very first time the cis,cis-isomer of dimethyl 3,3’-thiodiacrylate
on its spectroscopic data. The 1H NMR spectrum reveals the
12a with a melting point of 137-139 oC was crystallized out from
absence of methyl signal of ester and the cis-geometry of protons
the reaction mixture of the cis,cis-, cis,trans- and trans,trans-
of the olefinic bond is confirmed by the large coupling constant
isomers of dimethyl 3,3’-thiodiacrylate in methanol and the
(J = 10 Hz) between the adjacent protons. The same product was
stereochemistry of 12a was established unambiguously by means
obtained from the reaction between thiourea and ethyl propiolate.
of X-ray crystallographic method (see supporting information for
ORTEP plot) .23
The reaction of methyl propiolate in methanol with different
derivatives of thiourea afforded the same product 12, as a mixture
of isomers cis,cis-12a, cis,trans-12b and trans,trans-dimethyl
3,3’-thiodiacrylate 12.
When the mixture of thiourea (1 mmol) and methyl propiolate
(1.5 mmol) in methanol (2 mL) was allowed to stand at 0-5 oC, a
white colour solid with a melting point of 177-179 oC was
separated out after 10 h (Entry 1, Table 2).24 This solid was
insoluble in solvents such as chloroform and soluble in DMSO.
The spectroscopic analysis confirmed this compound as 2-amino-
4H-1,3-thiazin-4-one (13) (Scheme 3). This reaction when
carried out in ethyl lactate under the same conditions afforded 13
in 49% yield. Interestingly, there was no product formation when
the reaction was carried out at 0-5 oC by stirring in solvents such

4
Tetrahedron Letters
COOMe
COOMe
COOMe
COOMe
S
COOMe
H2O
rt
COOMe
R
R
S
S
S
N
N
H
H
COOMe
1a
12b
12c
12a
cis,cis
cis,trans
trans,trans
(Z,Z)
(E,Z)
(E,E)
Scheme 2. Reactions of thioureas with alkyl propiolates at room temperature.
Sporadic reports on the reactions of thiourea and methyl
propiolate are known in literature.25 Dallas et al. reported the
isomeric mixtures of the products with no cyclized compound by
placing together a mixture of thiourea and methyl propiolate in
methanol at room temperature for overnight.25b Kataev et al.
reported the formation of cyclized compound 13 along with a
mixture of two isomers 12 under same reaction conditions.25c
Similarly Kihiola and Teraola found only cis,cis-isomer as the
only product in the reaction of thiourea with ethyl propiolate with
no cyclized product.26
COOR1
H2N
S
S
CH3OH
N
H2N
NH2
0-5 oC
"on standing"
O
R' = Me, Et
13
Scheme 3. Reaction of thiourea with alkyl propiolates at 0-5 oC
In conclusion, a solvent tuning green approach has been
illustrated for the generation of a variety of thiazolidinone
derivatives by tuning water with environmentally benign ethyl
lactate as a co-solvent. The reactions were rapid and the products
were crystallized out from the reaction mixture in pure form. The
current catalyst-free protocol does not require purification steps
such as column chromatography or crystallization. The simplicity
of the experimental procedure and the ready accessibility of
acetylene derivatives and thiourea derivatives thus render this an
experimentally attractive method for the synthesis of
thiazolidinone derivatives. Moreover, the interesting findings on
the selective synthesis of 2-amino-4H-1,3-thiazin-4-one and
dimethyl 3,3’-thiodiacrylates are documented.
Furthermore the influence of solvent and temperature on the
reaction was also investigated and the results are summarized in
Table 3. It was observed that the nature of the solvent and
temperature were found to have an influence on the reaction
outcome. For example, when the reaction between thiourea and
methyl propiolate (Table 3, Entries 1, 3 and 4) was performed at
room temperature, the reaction was completed in 10-15 min to
provide the isomeric mixtures 12a, 12b and 12c of product
dimethyl 3,3’-thiodiacrylate in excellent combined yields 86-
o
93%. However, at 0-5 C, selective formation of 2-amino-4H-
1,3-thiazin-4-one (13) as a cyclized product occurred in ethyl
lactate or methanol with chemical yields of 49 and 77%,
respectively. The reactions of thiourea with dimethyl
acetylenedicarboxylate were also carried out (i) on standing at 0-
5
oC and (ii) under stirring at 0-5 oC. In both cases, the 1,3-
thiazinone derivative 2a was obtained in good yield.
Table 2. 1,3-Thiazinone 13 from acetylene monocarboxylates and thiourea.a
R’ in alkyl
propiolate
Reaction timeb
Yieldc
(%)
Entry
1
Thiourea
Solvent
MeOH
Product
(h)
H2N
S
N
Me
10
77
83
S
13
H2N
NH2
2
Et
MeOH
10
O
a Reactions were performed with thiourea (1 mmol) and alkyl propiolate (1.5 mmol) in methanol (2 mL) at 0-5 oC by allowing to stand.
b The product started separating out after 5 h of standing and went to completion in 10 h at 0 oC.
c Yield of pure and isolated product after filtration.
Table 3. Reaction of thiourea and methyl propiolate in different solvents.a
Entry
Solvent
Water
Temperature (oC)
Reaction time
10-15 min
12 h
Product
12a,b,c
13
Yieldb (%)
1
2
3
4
5
25
0-5
25
93c
Ethyl lactate
Water : EL
Methanol
Methanol
49
10-15 min
10-15 min
5-10 hd
86c
91c
77
12a,b,c
12a,b,c
13
25
0-5
a Reactions were performed with thiourea (1 mmol) and methyl propiolate (2 mmol) in 3 mL of solvent.
b Yield of pure and isolated product.
c Combined yield of pure cis,cis- and cis,trans- isomers of dimethyl 3,3’-thiodiacrylate.
d The product started separating out after five hours of standing and went to completion in ten hours at 0 oC.

Tetrahedron Letters
5
11 Ramazani, A.; Morsali, A.; Soudi, A. A.; Souldozi, A.;
Acknowledgments
Starikova, Z. A.; Yanovsky, A. Z. Kristallogr. 2003, 218,
33.
We gratefully acknowledge the financial support from the Council for
Scientific and Industrial Research [Project No. CSIR-01(2297)/09/EMR-
II], New Delhi. GC thanks CSIR for research fellowship.
12 (a) US Patent 4,775,677; (b) Hendrickson, J. B.; Rees, R.;.
Templeton, J. F. J. Am. Chem. Soc. 1964, 86, 107; (c)
Achenson, R. M.; Wallis, J. D. J Chem. Soc. Perkin Trans.
1, 1981, 415; (d) Gonbaria, M. H.; Ramazania, A.;
Souldozia, A. Phosphorus, Sulfur, and Silicon 2009, 184,
309.
References and Notes
†Supplementary Information (SI) available: [Spectroscopic
data of all products and crystallographic data tables of structures
11b and 12a].
13 Ramazani, A.; Kazemizadeh, A. R.; Ganjeie, B.; Bijan, A.
Asian J. Chem. 2005, 17, 2375.
14 (a) Choudhary, G.; Peddinti, R. K. Green Chem. 2011, 13,
276; (b) Choudhary, G.; Peddinti, R. K. Green Chem. 2011,
13, 3290.
1
2
(a) Keith, L. H.; Gron, L. U.; Young, J. L. Chem. Rev. 2007,
107, 2695; (b) SanderSon, K. Nature 2011, 469, 18; (c)
Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35,
686; (d) Jenck, J. F.; Agterberg, F.; Droescherc, M. J. Green
Chem. 2004, 6, 544.
15 Procedure for the synthesis of Thiazolidines 2-11: Thiourea
derivative (1, 2 mmol) was dissolved in 2 mL of a mixture
(see Table 1) of ethyl L-lactate and water. To this dialkyl
acetylenedicarboxylate was added and the contents were
stirred. A solid product was formed after a few minutes
(Table 1), which was then filtered and washed with water. In
case of oily product, the solvent was decanted and the
residue was subjected to silica gel column chromatography
(Hexanes/ethyl acetate: 90/10). All known compounds were
(a) Capello, C.; Fischer, U.; Hungerbühler, K. Green Chem.
2007, 9, 927; (b) Reichardt, C. Solvents and Solvent Effects
in Organic Chemistry, Wiley-VCH, Weinheim, 2003; (c)
Buncel, E.; Stairs, R.; Wilson, H. The Role of the Solvent in
Chemical Reactions, Oxford University Press, Oxford, 2003;
(d) Clark, J. H.; Tavener, S. J. Org. Process Res. Dev. 2007,
11, 149.
1
characterized by using H NMR and 13C NMR and the data
3
4
(a) Organic Reactions in Water, ed. Lindström, U. M.,
lackwell, Oxford, UK, 2007; (b) Zhang, X.; Jia X.; Wang J.;
Fan X. Green Chem. 2011, 13, 413; (c) Butler, R. N.;
Coyne, A. G. Chem. Rev. 2010, 110, 6302.
was compared with that of reported compounds.11-13
16 CCDC No. 833030.
17 PCT/EP2010/063071, patent number WO 2011/029803 A1.
(a) Nelson, W. M. Green Solvents for Chemistry:
Perspective and Practice, Oxford University Press, Oxford,
2003; (b) Jessop, P. G. Green Chem. 2011, 13, 1391; (c)
Adams, D. J.; Dyson, P. J.; Taverner, S. J. Chemistry in
Alternative Reaction Media, John Wiley & Sons Ltd,
Chichester, 2004; (d) Mikami, K. Green Reaction Media in
Organic Synthesis, Wiley-Blackwell, Oxford, 2005.
18 Temple, C.; Wheeler, G. P.; Comber, R. N.; Elliot, R. D.;
Montgomery, J. A. J. Med. Chem. 1983, 26, 1614.
19 Campaigne, E.; Nargund, P. K. J. Med. Chem. 1964, 7, 132.
20 Ingarsal, N.; Amutha, P.; Nagarajan, S. J. Sulfur Chem. 2006,
27, 455.
21 Koketsu, M.; Tanaka, K.; Takenaka, Y.; Kwong, C. D.;
5
6
(a) Bennett, J. S.; Charles, K. L.; Miner, M. R.; Heuberger,
C. F.; Spina, E. J.; Bartels, M. F.; Foreman, T. Green Chem.
2009, 11, 166; (b) Fukukawa, Ken-ichi; Shibasaki, Y.;
Ueda, M. Polymer Journal, 2004, 36, 489; (c) Nikles, S. M.;
Piao, M.; Lane, A. M.; Nikles, D. E. Green Chem. 2001, 3,
109; (d) Aparicio, S.; Alcalde, R. Green Chem. 2009, 11, 65.
Ishihara, H. Eur. J. Pharm. Sci. 2002, 15, 307.
22 Procedure for the synthesis of Dimethyl 3,3’-thiodiacrylate
(12): Thiourea (1a, 1 mmol) was dissolved in 3 mL of water
or methanol. To this, alkyl propiolate (2 mmol) was added
and the contents were stirred. A solid product (a mixture of
12a, 12b and 12c) was formed after a few minutes, which
was then filtered and washed with water and dried under
vacuum (89% yield).
(a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol,
L.; Machado, P. Chem. Rev. 2009, 109, 4140; (b) Balaban,
A. T.; Oniciu, D. C.; Katritzky, A. R. Chem. Rev. 2004, 104,
2777; (c) Wipf, P.; Fritch, P.C. Tetrahedron Lett. 1994, 35,
5397; (d) Shih, M.-H.; Ke, F.-Y. Bioorg. & Med. Chem.
2004, 12, 4633.
23 CCDC No. 833532.
24 Procedure for the synthesis of 2-Amino-4H-1,3-thiazin-4-
one (13): A solution of thiourea (1a, 1 mmol) in methanol (2
mL) was cooled to 0-5 oC. To this, alkyl propiolate (1.5
mmol) was added and the resultant solution was kept in the
refrigerator at 0-5 oC. After 5 h, the product could be seen as
white solid. In another 5 h the product was formed
completely and at that time the solid was filtered and washed
with water and dried under vacuum.
7
8
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(a) Lown, J. W.; Ma, J. C. N. Can. J. Chem. 1967, 45, 939;
(b) Winterfeldt, E.; Nelke, J. M. Chem. Ber. 1967, 100,
3671.
9
(a) Hendrickson, J. B.; Rees, R.; Templeton, J. F. J. Am.
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25 (a) Danilkina, N. A.; Mikhailov, L. E.; Ivin, B. A. Russ. J.
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10 (a) Short, F. W.; Littleton, B. C.; Johnson, J. L. Chem. Ind.
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26 Kihiola, Y.; Teraola, A. Chem. Pharm. Bull. 1968, 16, 1351.