Synthetic modification of 1,3-thiazolidin-4-one 1,1-dioxides

Article abstract of DOI:10.1080/10426507.2013.787998

The reactivity of EWG (electron withdrawing group)-activated methylene group in 1,3-thiazolidin-4-one 1,1-dioxides were investigated. Novel derivatives of 1,3-thiazolidin-4-one 1,1-dioxides were prepared (the heterocyclic core was modified with carboxamid

Full text of DOI:10.1080/10426507.2013.787998

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Phosphorus, Sulfur, and Silicon and the Related
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Synthetic modification of 1,3-thiazolidin-4-one 1,1-
dioxides
Dymytrii Listunov a b , Kirill Popov a b , Yulian Volovenko a & Sergiy Popov b
a Organic Synthesis Laboratory, Department of Chemistry, Taras Shevchenko National
University of Kyiv, Kyiv, 01033, Ukraine
b Spectrum Info Ltd, 5 Murmanska str., Kyiv, 02094, Ukraine
Accepted author version posted online: 05 Apr 2013.
To cite this article: Dymytrii Listunov , Kirill Popov , Yulian Volovenko & Sergiy Popov (2013): Synthetic modification of 1,3-
thiazolidin-4-one 1,1-dioxides, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:10.1080/10426507.2013.787998
To link to this article: http://dx.doi.org/10.1080/10426507.2013.787998
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Synthetic modification of 1,3-thiazolidin-4-one 1,1-dioxides
Dymytrii Listunov1,2*, Kirill Popov1,2, Yulian Volovenko1 and Sergiy Popov2
1Organic Synthesis Laboratory, Department of Chemistry, Taras Shevchenko National
University of Kyiv, Kyiv 01033, Ukraine
2Spectrum Info Ltd, 5 Murmanska str., Kyiv 02094, Ukraine
*E-mail: listunov_d@meta.ua
O
O
H
O
NH2
N
KMnO4
AcOH
O
N
PhH
S
+
+
S
HS
O
OH
reflux
O
4
Abstract
The reactivity of EWG (electron withdrawing group)-activated methylene group in 1,3-
thiazolidin-4-one 1,1-dioxides were investigated. Novel derivatives of 1,3-thiazolidin-4-one 1,1-
dioxides were prepared (the heterocyclic core was modified with carboxamide and
carboxthioamide moieties as carbonyl group analogues). The products, which have functional
groups for possible future modifications, are described and characterized.
Introduction
The structural and therapeutic diversity, coupled with commercial viability, of small
heterocyclic molecules has fascinated organic and medicinal chemists for a long period of time.
Amongst the heterocyclic systems, 1,3-thiazolidin-4-one 1,1-dioxides are a biologically
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important scaffold which is known to be important for display of several biological activities.
Some of the prominent biological responses attributed to this skeleton are cytotoxicity [1] (1),
CNS-mediators inhibition [2] (2) and antiproliferation [3] (3).
This diversity in the biological response profiles of 1,3-thiazolidin-4-one 1,1-dioxides
attracts the attention of many researchers to explore the possibility of the use this scaffold in the
design of multifunctional drug-like molecules [4, 5, 6, 7, 8, 9].
The desired compounds are being synthesized by a cyclization reaction [10, 11]. This
method is limited by the availability of the corresponding mercaptoacetic acid and the stability of
functional groups in carbonyl - and amino components under the reaction conditions. That is
why not only the synthesis, but also the post-synthetic modification of a heterocyclic system is
very important. So far, insufficient attention has been paid to the synthetic modification of the
1,3-thiazolidin-4-one 1,1-dioxides [9, 12, 13, 14]. However, the structure of these scaffolds
enables us to introduce different substituents in the fifth position, such as carbonyl group
equivalents including the carboxamide group. Moreover, this makes it possible to prepare the
molecules with pre-determined biological properties.
Results and discussion
2,3-diphenyl-1,3-thiazolidin-4-one (4) 1,1-dioxide was chosen as a model compound.
Compound 4 was obtained by three-component reaction of aniline, mercaptoacetic acid and
benzaldehyde followed by subsequent oxidation of 2,3-diphenyl-1,3-thiazolidin-4-one [12, 15]
(Scheme 1).
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It is well-known that the carbonyl group, or its equivalents, are amongst the most frequently used
functional groups in synthetic organic chemistry and that is the reason we decided to obtain some
carbonyl derivatives. DMF-DMA (N,N-dimethylformamide dimethyl acetal), POCl3/DMF,
triethylformate, phenyl isocyanate and phenyl isothiocyanate and benzoic acid in the presence of
a coupling additive (Scheme 2) were chosen for modification.
The starting compound 4 easily forms enamino-derivative (5) in DMF at room temperature
(Scheme 3).
Under Vilsmeier-Haack reaction conditions we didn’t obtain compound 5* instead the main
product was identified as 5.
The product 6 was obtained by the treatment of model compound with triethyl
orthoformate in acetic anhydride as a solvent over 5 h (Scheme 4).
1
In the H NMR spectra of derivatives 5 and 6 we could see the anticipated difference in
chemical shifts for proton at the double bond (0.5 ppm), that may be explained by differences in
the electronegativities of nitrogen and oxygen.
The carboxylic group is a starting motif for the synthesis of a variety of other derivatives such as
esters, amides, hydrazones. 1,3-Thiazolidin-4-one 1,1-dioxide also readily reacts with
electrophiles such as phenyl isothiocyanate and phenyl isocyanate. As a result, the corresponding
amide 7 and thioamide 8 were obtained (Scheme 5).
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It should be noted, that compound 4 can be acylated by arylcarboxylic acids in the presence of
coupling agents (Scheme 6). The best result was obtained with the EDC/DMAP system (Table
1).
Experimental
General data. Solvents were purified according to standard methods [16]. All commercially
13
available chemicals were purchased from Aldrich and Merck. The1H-NMR (400 MHz) and C-
NMR (100MHz) spectra were recorded on a Varian Gemini spectrometer, using DMSO-d6. All
chemical shifts are reported in ppm relative to TMS. IR spectra were recorded on spectrometer
Nicolet Nexus 470 in tablets KBr. Mass spectra were recorded on a VG micro mass 7070H
spectrometer in chemical ionization mode (APCI). Melting points were determined through a
Fisher–Johns apparatus and are uncorrected. Elemental analyses (C, H, N) determined by means
of a Perkin–Elmer 240 CHN elemental analyzer.
5-[(Dimethylamino)methylidene]-2,3-diphenyl-1,3-thiazolidin-4-one 1,1 – dioxide (5)
To a 1,3-thiazolidin-4-one 1,1-dioxide (1 mmol) in dry DMF (1 mL) DMF-DMA (1.3 mmol)
was added, and the mixture was stirred at room temperature overnight. The precipitate was
filtered off and washed with hexane. The product was obtained as white powder.
Yield 80%. M.p. 224-226ºС. 1Н NMR (ppm): 3.23 (s, 3Н), 3.30 (s, 3Н), 6.51 (s, 1Н), 7.05-
7.45 (m, 10Н), 7.73(s, 1Н). 13C NMR (ppm): 41.5, 47.1, 78.7, 92.5, 124.1, 124.2, 128.2, 128.3,
128.3, 128.4, 128.4, 128.5, 128.5, 129.3, 131.1, 137.3, 152.4, 162.7. MS: m/z 343.2 (M+1). Anal.
calcd. for C18H18N2O3S: C, 63.14%; H, 5.3%; N, 8.18%. Found: C, 63.11%; H, 5.28%; N, 8.19%
5 -(Ethoxymethylidene) - 2, 3 - diphenyl -1,3-thiazolidin-4-one 1,1 – dioxide (6)
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The mixture of 1,3-thiazolidin-4-one 1,1-dioxide (1 mmol), triethyl orthoformate (5 mmol)
and acetic anhydride (5 mmol) was refluxed for 5 h, after this the mixture was cooled down. The
precipitate was filtered off and washed with hexane. The product was obtained as white powder.
1
Yield 75%. M.p. >250ºС. Н NMR (ppm): 1.32 (t, J = 7.2 Hz, 3Н), 4.59 (q, J = 6.8 Hz, 2Н),
6.69 (s, 1Н), 7.15-7.43 (m, 10Н), 8.23 (s, 1Н). 13C NMR (ppm): 15.2, 74.2, 79.6, 106.3, 125.0,
126.3, 128.6, 128.6, 128.7, 128.7, 128.7, 128.7, 128.8, 129.6, 129.7, 136.2, 160.1, 165.1. MS:
m/z 344.1 (M+1). Anal. calcd. for C18H17NO4S: C, 62.96%; H, 4.99%; N, 4.08%. Found: C,
62.98%; H, 4.97%; N, 4.1%.
4-Oxo-N,2,3-triphenyl-1,3-thiazolidine-5-carboxamide 1,1-dioxide (7)
To a solution of DBU (1 mmol) in dry DMF (1 mL) solution of the 1,3-thiazolidin-4-one 1,1-
dioxide (1 mmol) and phenyl isocyanate (1 mmol) in dry DMF (1.5 mL) were added. The
mixture was stirred overnight and then 20 mL 5% HCl were added, the precipitate was filtered
off, washed with water and dried. The product was obtained as white powder.
Yield 80%. M.p. 203-205ºС. 1Н NMR (ppm): 7.26-7.47 (m, 15Н), 7.82-7.84 (m, 2Н), 12.51
(s, 1Н). 13C NMR (ppm): 72.6, 79.2, 122.1, 122.2, 122.6, 122.7, 124.5, 124.9, 125.2, 127.3,
127.3, 127.6, 128.5, 128.6, 130.3, 130.3, 131.8, 131.9, 139.7, 143.3, 161.5, 162.6. MS: m/z 407.1
(M+1). Anal. calcd. for C22H18N2O4S: C, 65.01%; H, 4.46%; N, 6.89%. Found: C, 65.03%; H,
4.47%; N, 6.87%.
4-Oxo-N,2,3-triphenyl-1,3-thiazolidine-5-carbothioamide 1,1-dioxide (8)
To a solution of DBU (1 mmol) in dry DMF (1 mL) solution of the 1,3-thiazolidin-4-one 1,1-
dioxide (1 mmol) and phenyl isothiocyanate (1 mmol) in dry DMF (1.5 mL) were added. The
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mixture was stirred overnight and then 20 mL 5% HCl were added, the precipitate was filtered
off, washed with water and dried. The product was obtained as white powder.
Yield 85%. M.p.168-170ºС. 1Н NMR (ppm): 7.22-7.44 (m, 15Н), 7.81-7.83 (m, 2Н), 12.71
(s, 1Н). 13C NMR (ppm): 71.9, 83.6, 122.9, 123.0, 124.9, 125.1, 125.1, 125.9, 126.8, 126.9,
127.4, 127.5, 128.8, 128.9, 130.6, 130.7, 132.2, 132.2, 139.3, 144.1, 160.9, 168.59. MS: m/z
423.3 (M+1). Anal. calcd. for C22H18N2O3S2: C, 62.54%; H, 4.29%; N, 6.63%. Found: C,
62.56%; H, 4.30%; N, 6.65%.
5-(2-Chloro-4-fluorobenzoyl)-2,3-diphenyl-1,3-thiazolidin-4-one 1,1-dioxide (9)
The mixture of 1,3-thiazolidin-4-one 1,1-dioxide (1 mmol), 2-chloro-4-fluorobenzoic acid (1
mmol), ЕDC (1 mmol), DMAP (1 mmol), DMF (3 mL) was stirred at room temperature for 120
h, then water was added and the precipitate was filtered off, washed with 5% HCl and dried. The
product was obtained as white powder.
1
Yield 70%.M.p.158-160ºС. Н NMR (ppm): 6.45 (s, 1Н), 7.03-7.56 (m, 14Н).13C NMR
(ppm): 79.1, 113.9, 114.2, 123.0, 124.4, 124.5, 124.7, 126.7, 127.5, 128.1, 128.4, 128.5, 128.5,
128.6, 128.6, 129.1, 129.4, 129.7, 130.1, 163.9, 173.3, 193.0. MS: m/z 444.0 (M+1). Anal. calcd.
for C22H15ClFNO4S: C, 59.53%; H, 3.41%; N, 3.16%. Found: C, 59.55%; H, 3.43%; N, 3.14%.
Conclusions
The possible ways of synthetic modification of 1,3-thiazolidin-4-one 1,1-dioxides were
described. DMF-DMA, POCl3/DMF, triethyl orthoformate, phenyl isocyanate and phenyl
isothiocyanate, benzoic acid in the presence of coupling reagents were used as electrophilic
reagents.
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Acknowledgments
We are grateful to Spectrum Info Ltd. for financial support of this research.
References and notes
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609
Figure 1. Some 1,3-thiazolidin-4-one 1,1-dioxides which demonstrate high biological activity
O
OH
H
O
O
O
N
O
O
NH
C18H37
N
N
N
S
O
S
S
O
O
O
O
O
O
O
Cl
1
2
3
Scheme 1. Synthesis of a model compound
O
O
H
O
NH2
N
KMnO4
AcOH
O
N
PhH
S
+
+
S
HS
O
OH
reflux
O
4
Scheme 2. Possible ways of modification
8
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O
Ph
N
N
O
N
O
O
S
S
Ph
O
6
O
Ph
O
Ph
O
Ph
N
5
O
S
Ph
O
O
X
4
Ph
N
Ph
N
H
O
S
Ph
O
7,8
O
O
Ph
N
Ar
O
S
Ph
O
9
X = O (7), S (8)
Ar = 2-Cl, 4-F-Ph (9)
Scheme 3. Synthesis of enamino derivative of 5
Cl
O
O
Ph
POCl3
DMF
DMADMF/DMF
Ph
N+
N
N
Ph
N
N
S
S
O
O
S
O
Ph
Ph
O
O
Ph
O
An-
4
5
5*
Scheme 4. Synthesis of 6
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O
O
(EtO)3CH
Ac2O
Ph
Ph
N
N
O
S
S
O
O
Ph
Ph
O
O
4
6
Scheme 5. Synthesis corresponding amide and thioamide
O
O
X
Ph
N
X
Ph
N
Ph
N
Ph
N
S
DBU
O
H
S
O
Ph
O
Ph
O
7,8
4
X=O(7) ,S (8)
Scheme 6. The acetylation of 4
O
O
O
ArCO2H
Ph
Ph
N
N
Ar
S
S
EDC/DMAP
O
O
Ph
Ph
O
O
4
(90%)
9
Ar=2-Cl,4-F-Ph
Table 1.
Reagent (solvent DMF) Time, h Yield of product, %
CDI
120
120
120
Not detected
EDC
30
90
EDC/DMAP
10
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