Cyclocondensation of thioamides and haloacetic acid derivatives provides only 4-thiazolidinones; Isomeric 5-thiazolidinones were not observed

Article abstract of DOI:10.1080/00397911.2013.800551

Cycloaddition of intermediates formed from the nucleophilic addition of aryl isothiocyanate to acidic cyanomethylenes and -halocarbonyl compounds gave only 4-thiazolidinones. 5-Thiazolidinones were not observed. Cyano-(4-oxo-3-phenylthiazolidin-2-ylidene)-acetic acid ethyl ester (1) and cyano-[5-(4-methoxybenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]-acetic acid ethyl ester (2a) also were shown to exhibit moderate antiviral activity. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.800551

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The Cyclocondensation of Thioamides and Haloacetic
Acid Derivatives Provides Only 4-Thiazolidinones;
Isomeric 5-Thiazolidinones were Not Observed
Danylo Kaminskyy a , Andrzej K. Gzella b & Roman Lesyk a
a Department of Pharmaceutical, Organic and Bioorganic Chemistry , Danylo Halytsky Lviv
National Medical University , Pekarska , Lviv , Ukraine
b Department of Organic Chemistry , Poznan University of Medical Sciences , Grunwaldzka ,
Poznań , Poland
Accepted author version posted online: 27 Aug 2013.
To cite this article: Synthetic Communications (2013): The Cyclocondensation of Thioamides and Haloacetic Acid Derivatives
Provides Only 4-Thiazolidinones; Isomeric 5-Thiazolidinones were Not Observed, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.800551
To link to this article: http://dx.doi.org/10.1080/00397911.2013.800551
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The cyclocondensation of thioamides and haloacetic acid derivatives provides only
4-thiazolidinones; isomeric 5-thiazolidinones were not observed
Danylo Kaminskyy1, Andrzej K. Gzella2, Roman Lesyk1
1Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky
Lviv National Medical University, Pekarska, Lviv, Ukraine, 2Department of Organic
Chemistry, Poznan University of Medical Sciences, Grunwaldzka, Poznań, Poland
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky
Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine Tel.: +38 032
2757734; Email: dr_r_lesyk@org.lviv.net
Abstract
Cycloaddition of intermediates formed from the nucleophilic addition of aryl
isothiocyanate to acidic cyanomethylenes and α-halocarbonyl compounds gave only 4-
thiazolidinones. 5-Thiazolidinones were not observed. Cyano-(4-oxo-3-
phenylthiazolidin-2-ylidene)-acetic acid ethyl ester(1) and cyano-[5-(4-
methoxybenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]-acetic acid ethyl ester
(2a)also were shown to exhibit moderate antiviral activity.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
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KEYWORDS: 4-thiazolidinones, 5-thiazolidinones, cyclocondensation, X-ray.
INTRODUCTION
Among small-molecule heterocyclic compounds thiazolidinones are recognized in drug
design as privileged scaffolds. The various avenues of chemical transformations in the
generation of a diverse variety of pendants on the thiazolidinone scaffold led to
exploration of the multiple biological effects. The prominent success in thiazolidinone
field is related especially to 4-thiazolidinone derivatives.[1,2] Antimicrobial, anti-
inflammatory, antidiabetic, and anticancer activities are a few among many other
biological responses had been shown for this scaffold.[3-6] However, the reports about 5-
thiazolidinones as isomers of the above mentioned 4-thiazolidinones concerning both the
information about the synthetic protocols and biological activity data[7,8]are rather scarce.
The methylene carbon atom at the 4-position of 5-thiazolidinone possesses nucleophilic
activity and can attack an electrophilic center affording the 4-ylidene derivatives.[9] The
latter are of special interest due to crucial role of the presence and/or nature of the C-5
substituent of the 4-thiazolidinone core plays in their biological activity.[5,6,10]
One of the most prominent and referenced protocol for 2-ylidene thiazolidinones
synthesis is the cyclocondensation reaction of reactants bearing the N=C=S fragment
with α-halocarbonyl compounds.[9] However, there are conflicting data regarding the
cyclization reaction product of chloroacetyl chloride with in situ intermediate formed
from nucleophilic addition of aryl isothiocyanate to acidic cyanomethylenes (scheme 1).
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The target compounds have been previously reported as 2-ylidene-4-thiazolidinones[11–13]
or often as 2-ylidene-5-thiazolidinones.[14–17] In both cases the structures of compounds
were confirmed by IR, NMR spectroscopy and mass-spectrometry. Moreover, the
spectral data didn’t contradict with the presented structures. However, the datas didn’t
provide answersregardingthe positionof the carbonyl group, i.e. the formation of 4- or 5-
thiazolidinone moieties. Hence, the aim of the communication is to describe the synthesis
and the structures determination of the ylidene thiazolidinones.
RESULTS AND DISSCUSION
Based on the above mentioned approach, the thiazolidinone 1 was synthesized and
transformed into ylidene derivatives 2a-c (scheme 2) under Knoevenagel reaction
conditions (acetic acid medium in the presence of sodium acetate).
The cyclocondensation reaction was performed at room temperature in the DMF medium.
Single crystal X-ray diffraction study corroborated the structures of compounds as
presented on Scheme 2. The molecular structures of compounds 1 and 2a with labeling
schemes are shown in Figs. 1 and 2, respectively. Target compounds were the 4-
thiazolidinone derivatives instead of 5-oxo isomers as it was described previously.
Moreover the structure of compound 1 was presented [18] and obtained from the reaction
of 2,4-bis(carboethoxycyanomethylene)-1,3-dithietane with amine and phenyl isocyanate.
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As follows from the X-ray analysis, the asymmetric unit of 1 and 2a contains two
symmetry-independent molecules (Figs. 1 and 2), which differ slightly in their
conformation. In both compounds the dissimilarities concern the angular arrangement of
the (N)-phenyl ring as well as the positioning of the ethoxy group (O11, C12, C13
atoms). The latter group in molecule B of 1 exhibits orientational disorder. The atoms
O11, C12 and C13 occupy two alternative positions B and C. The atoms assigned to B
position have the site occupancy factor of 82% while that assigned to C position have the
factor of 18%. In 1 and 2a, the cyano group reveals an E configuration with respect to the
sulfur atom of the 1,3-thiazol-4-one system.
Chloroacetyl chloride and ethyl chloroacetate were used to study thiazolidinone ring
formation reaction under the same conditions. The reaction product was cyano-(4-oxo-3-
phenylthiazolidin-2-ylidene)-acetic acid ethyl ester (1) in both cases. Moreover, the
different non-thiazolidinone product was formed upon the reaction mixture heating.[13]
The primary antiviral assay of the compounds (1 and 2a) was performed according
toNIAID's Antimicrobial Acquisition and Coordinating Facility program at the
biodefense viruses panel (Dengue Virus Type 2, Respiratory Syncytial Virus, Rift Valley
Fever Virus, Venezuelan Equine Encephalitis Virus, Tacaribe Virus) and the respiratory
viruses panel (Flu A (H3N2, H1N1, H5N1), Flu B, SARS) in accordance with standard
protocols.[19] The results for each tested compound were reported as virus-inhibitory
concentration 50% endpoint – EC50, and cell-inhibitory concentration 50% endpoint –
CC50. The general selectivity index (SI) was calculated as a ratio of (EC50)/(CC50). The
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tested compounds showed low to moderate activity against Flu panel viruses with the
highest action on the Influenza Virus Type A H5N1(EC50 = 18 µM, CC50 = > 100 µM, SI
= >5.6 for compound 1) (data available in the Supporting information).
EXPERIMENTAL
Synthesis Of Cyano-(4-Oxo-3-Phenylthiazolidin-2-Ylidene)-Acetic Acid Ethyl Ester
(1)
The ethyl cyanoacetate (36 mmol) followed by phenyl isothiocyanate (36 mmol) were
added to a cold suspension of KOH (36 mmol) in dry DMF. The mixture was stirred at
room temperature for 12 h, then cooled to 0°C, treated with the chloroacetyl chloride (36
mmol) (method a) or ethyl chloroacetate (36 mmol) (method b) and left to stand for 24 h
at room temperature. The mixture was poured into ice-cold water, and the resulting
precipitate was filtered off, dried and crystallized from DMF-EtOH or acetic acid. Yield
86% (method a) and 84% (method b); mp 208-210°C (AcOH), lit. 210°C;[20]1H NMR
(400 MHz, DMSO-d6): 1.18 (t, J = 7.0 Hz, 3H, CH3), 4.07 (s, 2H, CH2S), 4.19 (q, J = 7.0
Hz, 2H, CH2), 7.38-7.42 (m, 2H, arom.), 7.47-7.55 (m, 3H, arom.).13C NMR (100 MHz,
DMSO-d6): 174.0, 172.9, 165.5, 135.3, 131.0, 129.8, 129.8, 112.6, 76.6, 61.6, 32.6, 14.7.
Anal. calcd. for C14H12N2O3S: C, 58.32; H, 4.20; N, 9.72; Found: C, 58.55; H, 4.38; N,
9.96. LC-MS: m/z (%) = 289.6 (98%, M++1).
General Procedure For Synthesis Of Cyano-(5-Ylidene-4-Oxo-3-Phenylthiazolidin-
2-Ylidene)-Acetic Acid Ethyl Esters (2a–C)
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A mixture of compound 1 (3 mmol), appropriate oxocompound (3 mmol) and anhydrous
sodium acetate (3 mmol) was refluxed for 3 h in glacial acetic acid (10 mL). The
resulting precipitate was filtered off, washed with water and EtOH and then recrystallized
with DMF : EtOH (1:2) mixture or AcOH.
Cyano-[5-(4-Methoxybenzylidene)-4-Oxo-3-Phenylthiazolidin-2-Ylidene]-Acetic
Acid Ethyl Ester (2a)
Yield 82%; mp 252-254°C (DMF : EtOH); 1H NMR (400 MHz, DMSO-d6): 1.23 (t, J =
6.5 Hz, 3H, CH3), 3.88 (s, 3H, OCH3), 4.24 (q, J = 7.0 Hz, 2H, CH2), 7.20 (d, J = 8.7 Hz,
2H, arom.), 7.50-7.58 (m, 5H, arom.), 7.74 (d, J = 8.7 Hz, 2H, arom.), 7.87 (s, 1H, CH-
arom).Anal. calcd. for C22H18N2O4S: C, 65.01; H, 4.46; N, 6.89. Found: C, 64.92; H,
4.35; N, 6.78. LC-MS: m/z (%) = 407.5 (95%, M++1).
SUPPORTING INFORMATION
Structural characterization, NMR, LC-MS spectral data for synthesized compounds,
crystal data and refinement details for 1 and 2a as well as data of primary antiviral assay
are available. Crystallographic data (CCDC-900752 for compound 1, CCDC-900753 for
compound 2a) have been deposited at the Cambridge Crystallographic Database Centre
(www.ccde.cam.ac.uk).
ACKNOWLEDGEMENT
We are grateful to Dr. Chris Tseng, from Division of Microbiology and Infectious
Diseases NIAID/NIH, Bethesda, USA, for in vitro evaluation of antiviral activity.
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Scheme 1. Synthetic protocol to the 4(5)-ylidene-5(4)-thiazolidinone formation.
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Scheme 2. Synthesis of 2,5-diylidene-4-thiazolidinones.
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Figure 1. Two symmetry-independent molecules (ORTEP plot) of 1 showing the atomic
labelling scheme. Non-H atoms are drawn as 30% probability displacement ellipsoids and
H atoms are drawn as spheres of an arbitrary size.
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Figure 2. Two symmetry-independent molecules (ORTEP plot) of 2a showing the atomic
labelling scheme. Non-H atoms are drawn as 30% probability displacement ellipsoids and
H atoms are drawn as spheres of an arbitrary size.
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