Electrogenerated base-promoted synthesis and antimicrobial activity of 2-imino-1,3-thiazolidin-4-one derivatives

Article abstract of DOI:10.1080/17415993.2016.1155588

Electrogenerated cyanomethylanions obtained by reduction of dry acetonitrile at a steel grid cathode were used to promote the addition of ethyl bromoacetate to thiourea derivatives. The reaction yields the corresponding 2-imino-1,3-thiazolidin-4-one. The

Full text of DOI:10.1080/17415993.2016.1155588

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Electrogenerated base-promoted synthesis and
antimicrobial activity of 2-imino-1,3-thiazolidin-4-
one derivatives
Beya Haouas, Taieb Saied, Hanen Ayari, Youssef Arfaoui, Mohamed Lamine
Benkhoud & Khaled Boujlel
To cite this article: Beya Haouas, Taieb Saied, Hanen Ayari, Youssef Arfaoui, Mohamed
Lamine Benkhoud & Khaled Boujlel (2016): Electrogenerated base-promoted synthesis and
antimicrobial activity of 2-imino-1,3-thiazolidin-4-one derivatives, Journal of Sulfur Chemistry,
DOI: 10.1080/17415993.2016.1155588
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Date: 08 March 2016, At: 01:41

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2016.1155588
Electrogenerated base-promoted synthesis and antimicrobial
activity of 2-imino-1,3-thiazolidin-4-one derivatives
Beya Haouasa,b, Taieb Saieda,b, Hanen Ayaria, Youssef Arfaouic, Mohamed Lamine
Benkhouda and Khaled Boujlela
aLaboratory of Analytic Chemistry and Electrochemistry, Department of Chemistry, Faculty of Science,
University of Tunis, El Manar, Tunisia; bDepartment of Chemistry and Applied Biology, National Institute of
Applied Sciences and Technology, Tunis Cedex, Tunisia; cLaboratory of Physical Chemistry of Condensed
Materials, Department of Chemistry, Faculty of Science, University of Tunis, El Manar, Tunisia
ABSTRACT
ARTICLE HISTORY
Received 11 October 2015
Accepted 14 February 2016
Electrogenerated cyanomethylanions obtained by reduction of dry
acetonitrile at a steel grid cathode were used to promote the addi-
tion of ethyl bromoacetate to thiourea derivatives. The reaction
yields the corresponding 2-imino-1,3-thiazolidin-4-one. The reaction
pathway was discussed based on the kinetic and thermodynamic
data obtained by computational methods. In addition, the biological
activity of these new compounds was also investigated.
KEYWORDS
Thiourea; thiazolidinone;
acetonitrile;
electrogenerated base;
antimicrobial activity
1. Introduction
Recently, a review of the development and biological activity of thiazolidinones was
reported.[1] These family of products may display a large spectrum of applications such as
anticancer, antioxidant, anti-HIV-1, and bactericidal agents.[2–4] This behavior has been
attributed to the presence of the N–C–S fragment. Several methods for the synthesis of
1,3-thiazolidin-4-ones are widely reported in the literature. The foremost synthetic route
to these heterocyclic compounds involves the condensation of an amine with a carbonyl
compound leading to the formation of an imine which undergoes attack by sulfur of thio-
glycolic acid, followed by intramolecular cyclization.[5–7] Another method was proposed
by Bollivia the reaction of thiourea derivatives with a halo acetic acid leading directly to
the corresponding two isomeric 2-imino-1,3-thiazolidin-4-one.[8]
CONTACT Beya Haouas
haouas.beya@yahoo.fr
Supplemental data for this article can be accessed here. http://dx.doi.org/10.1080/17415993.2016.1155588
© 2016 Taylor & Francis

2
B. HAOUAS ET AL.
Many papers describe the generation and the use of electrogenerated bases (EGBs) in
organic synthesis.[9,10] These bases are obtained by simple galvanostatic reduction of dry
solvents such as acetonitrile, dimethyl sulfoxide or dimethylformamide in the presence of
quaternary ammonium salts as supporting electrolyte. Some advantages associated with
the use of EGBs include excellent control of the base strength depending on the choice of
the solvent and the ability to adjust the amount of EGB by varying the current density and
the duration of the electrolysis.
Several compounds such as arylcarbamic esters, acyclic dithiocarbamates, N-benzylic
rhodanines,[11–13] oxazolidin-2-ones,2-(1,3-dithian-2-ylidene)-2-arylacetonitrile or 3-
benzyl-5-imino-4-thioxo-2-imidazolidinone are prepared by this procedure.[14–16]
Herein, we report the use of EGBs to provide a simple and efficient synthesis of 2-imino-
1,3-thiazolidin-4-one starting from thiourea derivatives and ethyl bromoacetate.
2. Results and discussion
The electrochemical behavior of some thiourea derivatives by cyclic voltammetry in a
solution of acetonitrile and tetrabutylammonium tetrafluoroborate (TBABF4) 0.1 M on a
platinum disk electrode shows that these compounds are reducible at −1.8 V vs SCE as a
reference (Table 1).
For this reason, thiourea derivatives should be introduced at the end of electroly-
sis according to the terminology of Feroci et al. to allow the reduction of acetonitrile
only.[17,18] Electrolysis of dry acetonitrile in the presence of supporting electrolyte leads
to the formation of cyanomethyl carbanion in situ stabilized by ion pairing with the Mg
cation generated from the anode oxidation.[19] In contrast, the use of a graphite anode
does not produce stabilizing cations for EGBs and the yield of compounds 4 decreases
dramatically. Elsewhere the change of the value of the current density or the nature of
supporting electrolyte has no influence on the yield of products 4.
EGBs whose conjugate acids have pKa value >30 (e.g. acetonitrile) may remove
the weakly acidic proton of N,N-disubstituted thiourea.[20] A subsequent nucleophilic
attack from the thiolate anion (I) on ethyl bromoacetate, added in solution, generates
the intermediate (II) that evolves to the corresponding 2-imino-1,3-thiazolidin-4-one by
intramolecular cyclization (Table 2).
If R1 is different from R2, intermediate (II) can be present in two tautomers T1 and T2
in equilibrium which may lead to cyclization products 4 or 4ꢀ respectively by cyclization
and loss of ethanol (Scheme 1). To confirm that the structure 4 rather than 4ꢀ is the main
product, we opted for the theoretical calculation using density functional theory (DFT) of
three compounds: 1f, 1h, and1k.
In this way, all calculations were carried out with 1h (where R1 = Me2N and R2 = Et)
by using the Gaussian09 program.[21] The geometry parameters for all the reactants, tran-
sition states, and products of the reaction were fully optimized using DFT with B3LYP
functional and the 6–31G +(d) basis set.[22,23] The optimized structural parameters for
Table 1. Potential reduction of thiourea derivatives in acetonitrile–TBABF4.
Substrates
1a
1b
1c
1d
Ep (V) vs SCE
−1.84
−1.80
−1.79
−1.86

JOURNAL OF SULFUR CHEMISTRY
3
Table 2. Synthesized 2-imino-1,3-thiazolidin-4-one compounds 4.
Entry
R1
R2
Products
Yielda (%)
Electrolysis time (min)
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Et
iPr
Ph
PhCH2
Ph
N(Me)2
N(Me)2
N(Me)2
PhCH2
Ph
Me
Et
iPr
4a
4b
4c
4d
4e
4f
4g
4h
4i
60
70
63
90
88
84
75
64
75
77
72
176
163
137
92
84
88
110
150
101
110
120
Ph
PhCH2
PhCH2
Ph
Et
PhCH2
Et
1j
1k
4j
4k
Et
aThe yield was calculated relative to the starting thiourea derivatives which are consumed com-
pletely during the reaction.
Scheme 1. Proposed mechanism for the preparation of products 4 or 4ꢀ via EGB-promoted reactions.
1h were used for the vibrational frequency calculations at a DFT level to characterize all
the stationary points as minima. On the basis of this treatment, the intermediate (II)(T1)
is thermodynamically more stable than (II)(T2) (ꢀE = 10.9 kcal mol−1) (Scheme 2).
The activation energy Ea2 for the transition state TS2 is lower than the activation energy
Ea1 for the transition state TS1. Therefore, we can conclude that substrate 4ꢀh is the kinetic
product, whereas 4h is the thermodynamic one. These interpretations are in good agree-
ment with our experimental results. The corrections of zero point energy (ZPE), thermal

4
B. HAOUAS ET AL.
Scheme 2. Energy profile of the transformation of the intermediate (I) of 1h calculated at the B3LYP/6-
31+G(d) level.
Table 3. Corrections of ZPE, thermal and free energies of reactants and products
at the B3LYP/6-31+G(d) level.
ꢀE + ZPE/(kcal mol−1
)
ꢀH°/(kcal mol−1
)
ꢀG°/(kcal mol−1
)
4f
0.0
7.1
0.0
8.8
0.0
7.2
0.0
7.3
0.0
9.0
0.0
7.4
0.0
6.2
0.0
9.3
0.0
6.7
4ꢀf
4h
4ꢀh
4k
4ꢀk
and free energies of the reactants and products reported in Table 3, show that compound
4h is thermodynamically the most stable.
The thermodynamic stability of 4h compared to 4ꢀh is probably due to the presence
of an expanded conjugated system and a lower repulsion between non-bonding pairs of
oxygen and those of the R2 substituent.
3. Biological activity
3.1. Bacterial strains and growth conditions
Test organisms include six Gram-negative bacterial strains: Escherichia coli (ATCC 25922),
Proteus mirabilis (ATCC 29906), Salmonella typhimurium (ATCC 14028), Shigella flexneri
(ATCC 29903), Enterobacter cloacae (ATCC 18147), and Pseudomonas aeruginosa ATCC
27853; and three Gram-positive bacterial strains; Staphylococcus aureus (ATCC 25923),
Listeria monocytogenes (ATCC 19118), and Bacillus cereus (ATCC 11778). All bacterial
strains were cultivated in Luria Bertani Medium (LB) (Oxoid Ltd, UK) at 37°C except for
Bacillus species, which were incubated at 30°C. Working cultures were prepared by inocu-
lating a loopful of each test bacteria in 5 ml of LB and then incubated at 37°C for 18 h. All
the bacteria tested were issued from both the international culture collections ATCC and
the local culture collection of Pasteur Institute of Tunisia.

JOURNAL OF SULFUR CHEMISTRY
5
3.2. In vitro antibacterial bioassay: agar well-diffusion method
The susceptibility of the synthesized compounds toward bacteria has been evaluated
against various Gram-negative and Gram-positive bacteria by a agar well-diffusion
method, as described by Murthy et al.[24] Briefly, a suspension (0.1 mL of 106 CFU/mL)
of each microorganism was spread using a sterile cotton swab on the surface of solid LB
media plates. Cylindrical plugs were removed from the agar plates by a sterile cork borer
(Pyrex, UK) to produce wells with a diameter of approximately 6 mm. On the other hand,
solutions of the test compounds were prepared in ethanol and adjusted at a concentration
of 20 mmol L−1 and then a 50-μL of each sample solution was added to the respective wells
and allowed to diffuse at room temperature for 2 h. Next, the plates were incubated for 18 h
at 37°C. Results were recorded by measuring the diameter inhibitory zones in mm, includ-
ing the well diameter. The minimal inhibitory concentration was defined as the lowest the
diameters of the zone of inhibition produced compared finally to those produced by the
commercial control antibiotics, Streptomycin B (15 μg/mL).
3.3. Results and discussion
The results of antibacterial activities of the newly synthesized heterocyclic compounds
are presented in Table 4. As a conclusion, it is obvious to conclude that all the tested
compounds possessed moderate to good antibacterial activity against Gram-positive and
Gram-negative bacteria, except for L. monocytogenes, P. mirabilis, and Shigella flexneri
where the size of their inhibition zones ranges from 8 to 15 mm.
On the basis of the inhibition zone against the bacteria test, compound 4a was found
to be the most effective against E. coli (ATCC 25922) and exhibited a high antibacterial
activity against P. aeruginosa (ATCC 27853). However, compounds 4b and 4c showed a
moderate activity towards Bacillus cereus (ATCC 11778), E. Cloacae (ATCC 18147), and
S. aureus (ATCC 25923). In addition, the results revealed that new compound 4d proved
to be weakly active against the tested microorganisms compared to other test compounds.
On the other hand, our investigations proved that the test of the newly synthesized hete-
rocyclic compounds show promising antibacterial properties in vitro comparable or even
better than those of the antibiotic streptomycin (positive control). To the best of our knowl-
edge, the mechanism of the test compounds antibacterial activity has not been elucidated.
Table 4. Antibacterial activities of iminothiazolidin-4-one compounds.
Disc-diffusion method
Strains
4a
4b
4c
4d
Escherichia coli ATCC 25922
Staphylococcus aureus ATCC 25923
Bacillus cereus ATCC 11778
12
11
9
9
9
15
Inactive
8
Inactive
9
15
11
Pseudomonas aeruginosa ATCC 27853
Enterobacter cloacae ATCC 18147
Proteus mirabilis ATCC 29906
Shigella flexneri ATCC 29903
Listeria monocytogenes ATCC 19118
Salmonella typhimurium ATCC 14028
18
Inactive
12
Inactive
Inactive
Inactive
8
Inactive
Inactive
Inactive
Inactive
Inactive
10
Inactive
10
Inactive
Inactive
Inactive
11
Inactive
Inactive
Inactive
Inactive
11

6
B. HAOUAS ET AL.
This study allows the creation of a bioactive compounds bank for the discovery and the
development of new innovative therapeutic agents.[25,26]
4. Conclusion
New electrochemical methodology under mild reaction conditions was proposed for the
electrosynthesis of 2-imino-1,3-thiazolidin-4-one. The reaction here described involves
the EGBs in the condensation reaction of thiourea derivatives with ethyl bromoacetate as
electrophile. The thiazolidinone compounds showed interesting antibacterial activities.
5. Experimental procedure
1
The electrolyses were carried out using a Tacussel type PJT 35-2 potentiotat. H NMR
and 13C NMR spectra were recorded using a Bruker Advance 300 MHz spectrometer in
CDCl3 with TMS as an internal standard. IR spectra were measured using a Bruker Alpha
ATR spectrometer; samples were dissolved in CHCl3. Mass spectra (EI, ionizing volt-
age 70 eV) were determined using a Thermofisher ITQ-900 DIP/GC-MS mass-selective
detector. Elemental analyses were performed on a Perkin-Elmer Model 240-B analyzer.
The N,N-disubstituted thiourea are synthesized according to the experimental protocol
reported by Perveen et al.[27]
Products 4a–4k were prepared following the above-described methodology. Electroly-
sis of 100 mL of dry acetonitrile in the presence of TBABF4 0.1 M as supporting electrolyte
was carried out under galvanostatic conditions (I = 80 mA) and maintained under an
inert atmosphere of nitrogen. The solution was placed in an undivided electrochemical
cell cooled at −20°C, with a stainless steel grid cathode (apparent area about 20 cm2) and
a magnesium rod as a sacrificial anode (9 cm2). After the consumption of 2,2 faradays per
mole of acetonitrile, the current imposed was switched off and immediately 4 × 10−3 mol
of N,N-disubstituted thiourea was added to the reaction medium. Finally, 5 × 10−3 mol of
ethyl bromoacetate was introduced and the solution was kept under stirring at room tem-
perature. Once the reaction was finished, the solvent was removed under reduced pressure.
The residue was extracted with ether and the organic phase dried over magnesium sulfate
and concentrated by evaporation. The resulting residue was chromatographed on a silica
gel column using petroleum ether/ethyl acetate (7/3 v/v) as eluent. Elemental analyses and
spectroscopic descriptions of compounds 4 are given below.
5.1. 4a: 3-Methyl-2-(methylimino)thiazolidin-4-one
1
m.p.: 27°C. (300 MHz, CDCl3): H NMR δ: 2.91 (s, 3H); 3.01 (s, 3H); 3.80 (s, 2H). 13C
NMR δ: 28.19; 31.58; 37.34; 153.18; 170.46. GC-MS: M+(m/z): 144; 115; 102; 74; 71; 69;
59. IR (cm−1, CHCl3) ν: 1700 (C O); 1630 (C N). Elemental analysis experimental: %C:
58.53; %H: 5.16; %N: 5.67. Calculated: %C: 58.39; %H: 5.28; %N: 5.24.
=
=
5.2. 4b: 3-Ethyl-2-(ethylimino)thiazolidin-4-one
m.p.: 28°C. (300 MHz, CDCl3): 1H NMR δ: 1.05 (t, J = 7.10, 3H); 1.15 (t, J = 7.10, 3H);
3.23 (q, J = 7.10, 2H); 3.01 (q, J = 7.10, 2H); 3.72 (s, 2H). 13C NMR δ: 12.21; 15.51; 32.29;

JOURNAL OF SULFUR CHEMISTRY
7
37.60; 46.72; 150.86; 171.10. GC-MS: M+ (m/z): 172; 157; 129; 116; 101; 83; 69; 55. IR
(cm−1, CHCl3) ν: 1740 (C O); 1650 (C N). Elemental analysis experimental: %C: 48.9;
%H: 6.85; %N: 15.77. Calculated: %C: 48.81; %H: 6.90; %N: 15.89.
=
=
5.3. 4c: 3-Isopropyl-2-(isopropylimino)thiazolidin-4-one
m.p.: 37°C. (300 MHz, CDCl3): 1H NMR δ: 1.30 (d, J = 7.10, 6H); 1.40 (d, J = 7.10, 6H);
3.97 (s, 2H); 3.67 (m, 2H). 13C NMR δ: 18.43; 22.48; 46.79; 51.23; 51.29; 165.02; 171.29.
GC-MS: M+ (m/z): 200; 157; 114; 69. IR (cm−1, CHCl3) ν: 1745 (C O); 1660 (C N).
Elemental analysis experimental: %C: 53.95; %H: 8.01; %N: 14.04. Calculated: %C: 53.97;
%H: 7.99; %N: 13.99.
=
=
5.4. 4d: 3-Phenyl-2-(phenylimino)thiazolidin-4-one
m.p.: 66°C. (300 MHz, CDCl3): 1H NMR δ: 3.50 (s, 2H); 7.01–7.70 (m, 10H). 13C NMR
δ: 33.05; 121.04; 124.42; 136.14; 148.94; 156.31; 172.02. GC-MS: M+ (m/z): 268; 267; 165;
105; 137; 77; 51. IR (cm−1, CHCl3) ν: 1740 (C O); 1650 (C N); 1620 (C C). Elemental
analysis experimental: %C: 67.07; %H: 4.31; %N: 10.53. Calculated: %C: 67.14; %H: 4.47;
%N: 10.44.
=
=
=
5.5. 4e: 3-Benzyl-2-(benzylimino)thiazolidin-4-one
1
m.p.: 107°C. (300 MHz, CDCl3): H NMR δ: 3.70 (s, 2H); 4.71 (s, 2H); 5.12 (s, 2H);
7.30–7.91 (m, 10H). 13C NMR δ: 32.05; 45.04; 54.90; 125.02; 127.00; 128; 129.01; 130.14;
138; 140; 156.31; 172. GC-MS: M+ (m/z): 296; 205; 106; 91; 77. IR (cm−1, CHCl3) ν: 1610
=
=
=
(C C); 1660 (C N); 1740 (C O). Elemental analysis experimental: %C: 68.71; %H: 5.28;
%N: 9.32. Calculated: %C: 68.90; %H: 5.40; %N: 9.45.
5.6. 4f: 3-Benzyl-2-(phenylimino)thiazolidin-4-one
m.p.: 76°C (300 MHz, CDCl3): 1H NMR δ: 3.71 (s, 2H); 5.10 (s, 2H); 7.02–7.70 (m, 10H).
13C NMR δ: 32.05; 48.09; 121.20; 125.05; 127.02; 128.08; 129.01; 130.14; 138.05; 140.04;
156.31; 172.09. GC-MS: M+ (m/z): 282; 205; 191; 128; 114; 91; 77. IR (cm−1, CHCl3) ν:
=
=
=
1610 (C C); 1760 (C O); 1650 (C N). Elemental analysis experimental: %C: 68.01; %H:
4.92; %N: 10.15. Calculated: %C: 68.06; %H: 4.96; %N: 9.92.
5.7. 4g: 2-(2,2-Dimethylhydrazono)-3-phenylthiazolidin-4-one
m.p.: 174°C. (300 MHz, CDCl3): 1H NMR δ: 3.1 (s, 6H); 3.7 (s, 2H); 6.9–7.4 (m, 5H). 13
C
NMR δ: 30.05; 43.12; 120.84; 124; 129; 147; 151; 170. GC-MS: M+ (m/z): 235; 191; 158;
114; 101; 77. IR (cm−1, CHCl3) ν: 1730 (C O); 1640 (C N); C C (1608). Elemental
analysis experimental: %C: 56.28; %H: 5.33; %N: 17.66. Calculated: %C: 56.15; %H: 5.53;
%N: 17.86.
=
=
=

8
B. HAOUAS ET AL.
5.8. 4h: 2-(2,2-Dimethylhydrazono)-3-ethylthiazolidin-4-one
m.p.: 187°C. (300 MHz, CDCl3): 1H NMR δ: 1.15 (t, J = 7.12, 2H); 2.50 (s, 6H); 3.80 (s,
2H); 3.85 (q, J = 7.12, 2H). 13C NMR δ: 12.31; 27.62; 33.50; 39.29; 49.30; 160.77; 172.30.
GC-MS: M+ (m/z): 187; 158; 143; 130; 117; 102; 59. IR (cm−1, CHCl3) ν: C O (1740). 1630
(C N); Elemental analysis experimental: %C: 44.75; %H: 6.81; %N: 22.60. Calculated: %C:
44.90; %H: 6.94; %N: 22.45.
=
=
5.9. 4i: 3-Benzyl-2-(2,2-dimethylhydrazono)thiazolidin-4-one
Viscous oil. (300 MHz, CDCl3): 1H NMR δ: 2.30 (s, 6H); 3.5 (s, 2H); 4.80 (s, 2H); 7.20–7.4
(m, 5H). 13C NMR δ: 29.59; 33.44; 46.05; 47.99; 127; 128.54; 128.76; 129; 135.91; 160.31;
171. GC-MS: M+ (m/z): 249; 234; 205; 128, 114; 91; 68. IR (cm−1, CHCl3) ν: 1730 (C O);
1640 (C N); 1620 (C C). Elemental analysis experimental: %C: 57.73; %H: 6.15; %N:
16.76. Calculated: %C: 57.81; %H: 6.02; %N: 16.86.
=
=
=
5.10. 4j: 3-Ethyl-2-(benzylimino)thiazolidin-4-one
1
m.p.: 57°C. (300 MHz, CDCl3): H NMR δ: 1.18 (t, J = 7.12, 3H); 3.64 (q, J = 7.12,
2H); 3.71 (s, 2H); 5.10 (s, 2H); 7.20–7.81 (m, 5H). 13C NMR δ: 12.60; 33.58; 37.50;
50.14; 122.40; 124.42; 138.01; 147.89; 154.33; 171. GC-MS: M+ (m/z): 234; 219; 205; 157;
128; 91. IR (cm−1, CHCl3) ν: 1750 (C O) 1640 (C N); 1610 (C C); Elemental anal-
ysis experimental: %C: 61.61; %H: 5.92; %N: 11.73. Calculated: %C: 61.51; %H: 5.98;
%N: 11.96.
=
=
=
5.11. 4k: 3-Ethyl-2-(phenylimino)thiazolidin-4-one
m.p.: 48°C. (300 MHz, CDCl3): 1H NMR δ: 1.15 (t, J = 7.11, 3H); 3.66 (q, J = 7.11, 2H);
3.72 (s, 2H); 6.8–7.3 (m, 5H). 13C NMR δ: 15.51; 32.60; 38.05; 121.04; 124.42; 136.14;
148.94; 156.31; 172. GC-MS: M+ (m/z): 220; 205; 191; 143; 128; 114; 77; 69. IR (cm−1
CHCl3) ν: 1760 (C O); 1650 (C N); 1610 (C C). Elemental analysis experimental: %C:
60.05; %H: 5.32; %N: 12.91. Calculated: %C: 59.97; %H: 5.45; %N: 12.72.
,
=
=
=
Acknowledgements
The authors gratefully acknowledge the Ministry of Higher Education and Scientific Research
(MHESR) for the financial support through the lab LR99ES15 of Tunisia.
Disclosure statement
No potential conflict of interest was reported by the authors.
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