Efficient synthetic procedure to new 2-imino-1,3-thiazolines and thiazolidin-4-ones promoted by acetonitrile electrogenerated base

Article abstract of DOI:10.1039/c8nj01992d

A novel and convenient strategy is described for the regioselective conversion of N,N′-disubstituted thioureas and 1,2-dielectrophiles into the highly biologically valuable 2-imino-thiazoline and 2-imino thiazolidine-4-one derivatives. The synthesis proce

Full text of DOI:10.1039/c8nj01992d

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Efficient synthetic procedure to new 2-imino-1,3-
thiazolines and thiazolidin-4-ones promoted by
acetonitrile electrogenerated base†‡
Cite this:DOI: 10.1039/c8nj01992d
Beya Haouas,a Najwa Sbei,a Hana Ayari,a M. Lamine Benkhouda and
bc
Belen Batanero
*
Received 24th April 2018,
Accepted 11th June 2018
A novel and convenient strategy is described for the regioselective conversion of N,N0-disubstituted
thioureas and 1,2-dielectrophiles into the highly biologically valuable 2-imino-thiazoline and 2-imino
thiazolidine-4-one derivatives. The synthesis proceeds through a process with good yield promoted by
an electrogenerated base (EGB) obtained with high current efficiency.
DOI: 10.1039/c8nj01992d
rsc.li/njc
and developing new electrosynthetic routes to highly demanded
compounds.
1. Introduction
Despite the broad synthetic organic procedures already described,
4-Thiazolidinones and related heterocycles are intensively
there is still a need to develop new organic reactions, to allow explored for the design of new drug-like molecules.5,6 Despite
better connection of reactive functions and reagents. Electro- the variety of 4-thiazolidinone bearing compounds, the search for
chemistry is probably the key to introduce new reaction discoveries, new antibacterial, antiviral, anti-inflammatory,7 and antidiabetic
based on uncommon but promising organic intermediates to evolve agents8 is the main direction associated with the thiazolidinone
such unexplored chemical transformations.
framework. Nowadays this research area is mainly focused on
Electrogenerated radical anions and anions are basic reagents, the design of new anticancer agents.9 A positive perspective of
called EGBs, which can be used to deprotonate and to initiate 4-thiazolidinones is linked to a polypharmacological approach
many base catalyzed reactions.1 The use of EGBs in organic where the affinity towards various targets is regarded as an
synthesis is well documented.2 Radical anions as EGBs have advantage in the treatment of inflammation and cancer.10
great potential in synthesis, as demonstrated in the stereo- Apoptosis induced by 4-thiazolidinones has been demonstrated
selective cyclopropanation to homoquinones from phenacyl in various cancer cells.11,12 The 2-amino(imino)-4-thiazolidinones
carbenes, that we have recently highlighted.3 Moreover carbanions, are effective growth inhibitors of HT29 adenocarcinoma cells,13
that can be easily obtained at the cathode, are typical strong bases and human lung cancer cell lines H460,14 or fused as imidazo-
that can provide useful nucleophiles from acidic components [2,1-b]thiazole S100-inhibitors for cancer and autoimmune disease
of the reaction mixture. The preparative scaled reaction to treatment.15
3,4-disubstituted quinazoline-2-ones has been successfully promoted
by cyanomethyl anions as the EGB, starting from anilines.4
Currently, the search for compounds possessing combined
types of activities is of special interest, especially with simultaneous
This electrochemical strategy relies on the choice of the antiproliferative or cytostatic effects, such as the combination of
particular type of designed acidic substrates, difficult to be anticancer, antioxidant and anti-inflammatory activities. In this
deprotonated, which may leave many unexplored chemical field, the search for new 4-thiazolidinone compounds, and fused
reactivities. However our approach is mainly focused on yielding 2-imino-1,3-thiazolidine frameworks, with DNA binding activity16 or
demonstrated Alzheimer’s disease neurodegenerative inhibition
activity,17 is a promising direction to design, develop and scale
alternative electrochemical synthetic methodologies.
a
´
Laboratoire de Chimie Analytique et d’Electrochimie. Faculte des Sciences,
´
Universite Tunis El Manar, 2092 El-Manar (Tunis), Tunisia
b
The first reports on the synthesis of 2-imino-1,3-thiazolines
were published more than a century ago and comprise condensation
reactions of unsubstituted thioureas and a-haloketones that, under
acidic conditions and due to emerged isomerism problems, gave rise
to variable amounts of side-products.18 A general approach
toward 2-imino-1,3-thiazolidines involves the intramolecular
cyclization of N-(2-hydroxyethyl)thiourea derivatives in an acetic
´
´
Department of Organic Chemistry, University of Alcala, 28871 Alcala de Henares
(Madrid), Spain
c
´
´
´
´
Instituto de Investigacion Quımica ‘‘Andres M. del Rıo’’ (IQAR), University of
´
´
Alcala, 28871 Alcala de Henares (Madrid), Spain. E-mail: belen.batanero@uah.es
† Dedicated to Professor Fructuoso Barba on the occasion of his 75th birthday.
‡ Electronic supplementary information (ESI) available: Copies of the 1H and 13
NMR spectra, IR and MS of the new compounds 3 and 4 are provided. See DOI:
10.1039/c8nj01992d
C
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Scheme 2 Cathodic formation of 3-amino-crotonitrile anion.
Scheme 1 Outline of the synthetic procedure described in this paper.
is also formed at room temperature, by the nucleophilic attack of
the cyanomethyl anion to a new solvent molecule, as indicated in
Scheme 2.
medium or, alternatively, in the presence of triphenylphosphine
and diethyl azodicarboxylate.19 Recent multicomponent reactions
of aromatic a-haloketones, primary amines and phenyl isothio-
cyanate afforded 4-aryl-2-(N-phenylimine)thiazoles in a moderate
yield,20 which is only increased when the porcine trypsin enzyme
is used as a catalyst,21 or when 1,3-disubstituted thioureas are
exposed to 1,10-(ethane-1,2-diyl)dipyridinium bistribromide
(EDPBT).22
However, these moieties have also been prepared in a less
general approach starting from aziridines upon treatment with
thiocyanuric acid,23 from 2-vinylaziridines in the reaction with
phenyl-isothiocyanate,24 or from 1-(phenylthiocarbamoyl) aziridines
under acid catalysis.25 One effective literature entry to 2-imino-
1,3-thiazolines and thiazolidin-4-ones uses 1-arylmethyl-2-(bromo-
methyl)aziridines via ring transformation,26 which proceeds in a
straightforward manner giving a good yield.
At present, imino-thiazolidines have been regioselectively
synthesized via the base promoted cyclization of epoxy-sulfonamides
and heterocumulenes,27 and at the same time imino-thiazolidin-4-
ones have just been obtained through a three component tandem
annulation promoted by visible light.28
One of the most striking advantages of the electrochemical
processes to generate bases is the excellent control of the base
strength, depending on the choice of the solvent. Furthermore,
the amount of electrogenerated base (EGB) is a function of the
imposed current density and the duration of the electrolysis,
which can also be adjusted.29
With the aim of investigating the scope and limitations of
acetonitrile anions, as a strong EGB, in the synthesis of new
biologically active heterocyclic molecules, we focused now our
attention on using electrochemistry as a tool to prepare 2-(N-
substituted)imino-1,3-thiazoline moieties (3) and 2-(N-substituted)-
imino-1,3-thiazolidine-4-ones (4), as outlined in Scheme 1. The
result is herein reported as a novel and safe strategy for the
conversion of readily available substrates into these highly
valuable 2-imino-thiazolidine derivatives that proceeds through
a process with good yield and is promoted by a high current
efficiency EGB.
However, the use of low temperatures and sacrificial anodes,
such as magnesium or aluminium, in an undivided cell, avoids
to a large extent this undesired dimerization reaction. It occurs
because the subsequently formed magnesium cations, present in
solution, stabilize the cyanomethyl anions by ion-pair association.32
This fact allows, under these experimental conditions, the cyano-
methyl anion to act as an EGB, not as a nucleophile, and therefore
to be used as a promoter in the abstraction of protons from
substrates as amines, amides or similar weak acidic molecules.
The optimal quantity (equivalents) of EGB to get a complete
consumption of the starting substrate will depend on the
designed process, bearing in mind that, in the absence of a
proton donor, one equivalent of the cyanomethyl carbanion is
produced in a 1 F molꢀ1 process. Subsequently, the amount of
EGB in the catholyte will be controlled by the total circulated
charge through the electrochemical cell (solution).
Thioureas are versatile reagents that can be deprotonated by
cyanomethyl anions in a high extent, leading to a first stabilized
nitride (thiolate) (i), as indicated in Scheme 3. The needed
quantity of EGB to react with disubstituted thioureas (1) should
be twice the amount of 1, because both N–H bonds on 1 are
desirable to be activated by deprotonation, although not at the
same step. The experimental procedure involves, once the current
supplier is switched off, the provision of the corresponding
N,N0-disubstituted thiourea (1) to the reaction medium.
The freshly generated nitride (i), stabilized through an imino-
thiolate resonance form, attacks further an organic 1,2-dielectrophile
molecule (2), later introduced into the catholyte.
a-Halocarbonyl compounds are well known electro-reducible
substrates, both under protic and aprotic solvents. For this reason,
the presence of compounds 2 is avoided in the electrolytic solution
under the applied galvanostatic conditions, needed to produce
the EGB.
The formation of 3 starts with a nucleophilic thiolation reaction
to the C–Br bond on 2, followed by a new proton abstraction by EGB
that leads to a new nitride intermediate. After ring closure, the latter
provides the desired heterocycle. In the synthesis of compound 4,
the freshly prepared nitride (i) is acylated by the propionyl chloride
(2c), to afford an amide that is further deprotonated by a new EGB
2. Results and discussion
It is well established that the electrochemical reduction of molecule. Depending on the nature of 2, the final cyclization
acetonitrile, in the presence of a quaternary ammonium salt as evolves via an addition reaction to the ketone carbonyl group, or
a supporting electrolyte, yields the corresponding cyanomethyl via a nucleophilic substitution to the C–Br bond, leading
anion, a strong basic entity, with a pKa value in DMSO of ca. 32,30 respectively to 2-(N-substituted)imino-1,3-thiazoline moieties
capable of removing a weak acidic proton. When this reduction is (3) or 2-(N-substituted)imino-1,3-thiazolidine-4-ones (4).
performed at a platinum, graphite or stainless-steel cathode,
An interesting feature of this procedure is its regioselectivity.
under an argon atmosphere, the anion of 3-aminocrotonitrile31 In all cases only one regioisomer was formed during the reaction,
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Scheme 3 Mechanism proposal to 2-(N-substituted)imino-1,3-thiazolines (3) and 2-(N-substituted)imino-1,3-thiazolidin-4-ones (4).
Table 1 Obtained yields on heterocycles 3 and 4, in the reaction of
disubstituted thioureas (1) (1.0 mmol) with EGB (2.2 eq.) and dielectrophiles
2 (1 mmol). Electrolytic conditions: stainless steel cathode, magnesium
anode, (CH3CN/0,1 M TBABF4)
as the result of a first deprotonation of 1 (the more acidic NH
group when unsymmetrical thiourea is used). The electronic
effects of the substituents, that should stabilize (or not) the nitride,
will determine the easier proton abstraction from 1. Furthermore,
depending on the nature of the 1,2-dielectrophile (2), the latter will
be attacked by nitrogen or by a sulfur atom. No other heterocycles
were isolated, such as the plausible 1,3-disubstituted imidazole-2-
thione; the only by-product was 3-aminocrotonitrile.
Whereas a detailed mechanism proposal is above indicated,
the reaction was successfully extended to a variety of symmetrical
and unsymmetrical alkyl and aryl thioureas (1a–g).
The isolated yields on the 1,3-thiazoline products 3(a–h)
and 4(a, f, and g), formed from disubstituted thioureas 1(a–g)
(with alkyl: benzyl, ethyl and cyclohexyl, aryl: phenyl, and other
groups such as dimethylamino) and the three different 1,2-
dielectrophiles 2(a–c), are summarized in Table 1. The complete
characterization of these new compounds was performed according
to their spectroscopic and spectrometric properties.
Entry
R1
R2
R3
R4
%Yield 3
%Yield 4
1a
1b
1c
1d
1e
1f
1b
1f
1a
1f
Ph
Et
Cyclohexyl
Ph
Bn
Et
Et
Et
Ph
Bn
Me2N
Me2N
Ph
Ph
Bn
Ph
Ph
Me
Me
Me
Me
Me
Me
Ph
Ph
Cl
H
H
H
H
H
H
Me
Me
Me
Me
Me
68 (3a)
71 (3b)
70 (3c)
67 (3d)
76 (3e)
80 (3f)
83 (3g)
79 (3h)
—
—
—
—
—
—
—
—
—
Ph
Et
Bn
67 (4a)
74 (4f)
82 (4g)
Ph
Me2N
Cl
Cl
—
—
1g
The heterocyclization reaction that evolves to the thiazoline
ring is supported by the heteronuclear multiple bond correlation
(gradient HMBC), a two-dimensional spectrum (13C and 1H-NMR
data) of 3g, that is shown in Fig. 1. The two methylene hydrogen 141.7 ppm. Contrary to this correlation, the ethyl group at the
atoms of a benzyl group, directly joined to the nitrogen of the 3-position of the ring (–CH2– at 3.67 ppm) correlates properly,
imino function at the 2-position of the ring (that appear at according to a three-bond distance, with the quaternary sp2
d = 4.40 ppm) correlate, according to a two-bond distance, with carbon at 141.7 ppm, as well as the protons in the methyl group
quaternary sp2 carbon (at the ipso position) of the benzene ring at the 5-position of the ring (d = 1.94 ppm) which is also
(d = 147.1 ppm) rather than with the quaternary carbon at observed in the figure.
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Fig. 2 Electrolytic cell for acetonitrile reduction.
the supporting electrolyte was carried out under galvanostatic
conditions (I = 80 mA), maintained under an inert argon
atmosphere and cooled at 0 1C. The solution was placed in
an undivided electrochemical cell, with a stainless steel grid
cathode (apparent area about 20 cm2) and a magnesium rod as
a sacrificial anode (9 cm2) (Fig. 2).
The imposed current was switched-off after a charge of
520 coulombs was circulated through the cell (in a consumption
process of 1.0 faraday per mole of the desired acetonitrile anion
formed). Subsequently 5.4 ꢁ 10ꢀ3 mol of cyanomethyl anion were
obtained, and immediately 2.5 ꢁ 10ꢀ3 mol of N,N0-disubstituted
thiourea were added to the reaction medium.
Fig. 1 Two-dimensional HMBC correlation spectrum of 3g in CDCl3.
This EGB promoted procedure has many advantages to be
considered: (1) this is a regioselective synthesis whose steps
occur all into the one-pot electrochemical cell: once the cyano-
methyl anion is formed at the cathode surface, and the current
supplier is switched off, the consecutive addition of the corres-
ponding disubstituted thiourea and 1,2-dielectrophile proceeds
in the same beaker. (2) The use of toxic or dangerous reactants,
such as a transition-metal catalyst, needed in other 1,3-thiazoline
conventional processes, is suppressed because now the base is
electrogenerated ‘‘in situ’’. (3) The described procedure is quite
versatile and can be generalized to alkyl and aryl thioureas.
Depending on the starting 1,2-dielectrophile one can produce a
high variety of 1,3-thiazolines (3) or 1,3-thiazolidin-4-ones (4) in
good yield.
3.2 Preparation of 2-imino 1,3-thiazolines (3) and 2-imino
1,3-thiazolidin-4-ones (4)
After 1 h of stirring the EGB with thiourea (1), always under an
argon atmosphere at 0 1C, 2.7 ꢁ 10ꢀ3 mol of a 1,2-dielectrophile
(2) were introduced into the solution and it was further kept
under stirring for 2 h up to room temperature. Once the reaction
was finished, the solvent was removed under reduced pressure.
The residue was extracted with ether and the organic phase
was dried over anhydrous MgSO4 and concentrated by evaporation.
The resulting residue was purified by chromatography on a silica gel
60 (20 ꢁ 3 cm) column using petroleum ether/ethyl acetate (7/3 v/v)
as the eluent. Elemental analyses and spectroscopic descriptions of
the new compounds 3 and 4 are given below.
3. Experimental section
The electrolyses were carried out using a Tacussel type PJT 35-2
potentiotat and a DC-Power Promax Model FA-672 as a constant
current supply. The temperature was maintained constant at
0 1C by a cryostat Grant Model LTD 6G. IR spectra were
recorded as dispersions in KBr or NaCl films using a Brucker
Alpha ATR spectrophotometer. The mass spectra (EI, ionizing
voltage 70 eV) were obtained on a THERMOFISHER ITQ-900
spectrometer, with a DIP/GC-MSn mass-selective detector.
1H NMR and 13C NMR spectra were recorded using a Bruker
Advance 300 MHz spectrometer or a Varian Unity 500 MHz
spectrometer in CDCl3 solutions with tetramethylsilane (TMS)
as the internal standard. The chemical shifts are given in ppm.
Two-dimensional HMBC correlation NMR experiments were
performed in the Varian Unity 500 MHz spectrometer. Melting
points were measured on a Reichert Thermovar microhot stage
apparatus and are uncorrected. Elemental analyses were performed
on a Leco CHNS Model 932 analyzer.
4-Methyl-3-phenyl-2-(N-phenylimino)-1,3-thiazoline34 (3a).
Solid. m.p: 134–136 1C. IR (KBr) n = 3119, 2977, 1602, 1569,
1474, 1114, 1020, 693, 636 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d
1.85 (s, 3H), 5.60 (s, 1H), 7.05 (d, 2H, J = 7.8 Hz), 7.25 (t, 3H,
J = 7.8 Hz), 7.38 (t, 3H, J = 7.8 Hz), 7.50 (d, 2H, J = 7.8Hz).
13C NMR (CDCl3, 100 MHz): d 16.3, 94.2, 121.5, 122.5, 128.7,
129.6, 129.8, 135.1, 137.5, 152.2, 160.7. EI-MS: m/z (relative
intensity): 266(M+, 92), 265(M+ ꢀ1, 100), 251(4), 234(3), 226(2),
189(2), 163(1), 119(17), 104(1), 77(15).
2-(N-Benzylimino)-3-ethyl-4-methyl-1,3-thiazoline (3b). Solid.
m.p: 103–106 1C; IR (KBr) n = 3020, 2985, 1602, 1579, 1490, 1440,
1350, 1240, 1010, 750, 690 cmꢀ1 1H NMR (CDCl3, 400 MHz):
;
d 1.25 (t, 3H, J = 6.8 Hz), 2.04 (s, 3H), 2.57(s, 2H), 4.10 (q, 2H,
J = 6.8 Hz), 6.05 (s, 1H), 7.06 (d, 2H, J = 7.9 Hz), 7.15–7.35 (m,
3H). 13C NMR (CDCl3, 100 MHz): d 14.8, 17.1, 47.5, 64.2, 91.7,
121.5, 125.1, 125.4, 131.5, 138.7, 160.4. EI-MS: m/z (relative
intensity): 232(M+, 35), 119(100), 112(42), 77(47). Anal. calcd
The N,N0-disubstituted thioureas (1) were synthesized according
to the experimental protocol reported by Perveen et al.33
3.1 Electrochemical formation of a cyanomethyl anion
Electrolysis of a solution of dry acetonitrile (100 mL) and for C13H16N2S: C, 67.24; H, 6.90; N, 12.07; S, 13.79. Found: C,
tetrabutylammonium tetrafluoroborate (TBABF4) (0.1 M) as 67.20; H, 6.94; N, 12.06; S, 13.80.
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3-Cyclohexyl-4-methyl-2-(N,N-dimethylhydrazono)-1,3-thiazoline 1638, 1374, 1329, 1225, 1067, 769 cmꢀ1
(3c). Oil. H NMR (CDCl3, 500 MHz): d 1.18–1.38 (m, 4H), 1.64 (t, 300 MHz): d 1.74 (d, 3H, J = 6.9 Hz), 4.23 (q, 1H, J = 7.2 Hz),
4H, J = 10.3 Hz), 1.81(d, 2H, J = 14.7 Hz), 2.05 (s, 3H), 2.47 (s, 6H), 6.97 (d, 2H, J = 7.4 Hz), 7.15 (t, 1H, J = 7.2 Hz), 7.35 (t, 2H,
3.84 (bs, 1H), 5.40 (s, 1H). 13C NMR (CDCl3, 125 MHz): d 16.3, J = 7.7 Hz), 7.38–7.52 (m, 5H). 13C NMR (CDCl3, 75.4 MHz): d
Paper
;
1H NMR (CDCl3,
1
25.2, 26.3, 28.8, 47.2, 57.0 (N–CH(–CH2)–CH2), 94.6 (–CHQ), 135.7 20.0, 42.8, 121.2, 124.8, 128.2, 129.1, 129.3, 129.5, 135.1, 148.5, 154.2,
ꢀ
(QC–N–), 165.0 (–CQN–). EI-MS: m/z (relative intensity): 239(M+, 175.1. EI-MS: m/z (relative intensity): 282(M+, 100), 281(M+ ꢀ1, 73),
100), 224(4), 195(1), 182(4), 157(12), 142(5), 114(37), 100(11). Anal. 253(10), 194(26), 163(38), 118(6), 104(76), 91(14), 77(40), 51(29).
calcd for C12H21N3S: C, 60.30; H, 8.80; N, 17.60; S, 13.40. Found: C,
60.21; H, 8.84; N, 17.55; S, 13.39.
2-(N-Ethylimino)-5-methyl-3-phenyl-1,3-thiazolidin-4-one (4f).
Solid. m.p: 94–97 1C. IR (KBr) n = 3054, 2970, 1706, 1634, 1379,
1
4-Methyl-2-(N,N-dimethylhydrazono)-3-phenyl-1,3-thiazoline 1245, 765, 731, 688 cmꢀ1; H NMR (CDCl3, 300 MHz): d 1.15 (t,
(3d). Solid. m.p: 72–74 1C. IR (KBr) n = 3030, 2926, 1633, 1606, 3H, J = 7.2 Hz), 1.72 (d, 3H, J = 7.2 Hz), 3.31 (q, 2H, J = 7.2 Hz),
1
1592, 1487, 1449, 1357, 1027, 750, 698 cmꢀ1; H NMR (CDCl3, 4.20 (q, 1H, J = 7.2 Hz), 7.25 (d, 2H, J = 7.2 Hz), 7.35-7.48 (m, 3H).
500 MHz): d 2.04 (s, 3H) 3.09 (s, 6H), 5.30 (s, 1H), 7.02 (t, 1H, 13C NMR (CDCl3, 75.4 MHz): d 15.2, 19.9, 42.1, 47.2, 128.0, 128.6,
J = 7.3 Hz), 7.06 (d, 2H, J = 7.3 Hz), 7.32 (tt, 2H, J1= 7.9 Hz, 129.1, 135.3, 151.0, 174.9. EI-MS: m/z (relative intensity): 234(M+,
J2 = 2.0 Hz). 13C NMR (CDCl3, 125 MHz): d 14.6, 42.6, 88.4, 19), 233(M+ ꢀ1, 100), 219(4), 205(9), 191(4), 177(3), 151(12),
121.3, 122.7, 129.3, 136.6, 151.2, 155.3. EI-MS: m/z (relative 118(18), 104(7), 91(7), 77(11). Anal. calcd for C12H14N2OS: C,
intensity): 233(M+, 30), 190(100), 189(85), 156(4), 149(10), 61.54; H, 5.98; N, 11.97; S, 13.68. Found: C, 61.48; H, 6.01; N,
145(5), 115(5), 97(5), 77(9). Anal. calcd for C12H15N3S: C, 11.83; S, 13.62.
61.80; H, 6.44; N, 18.03; S, 13.37. Found: C, 61.77; H, 6.48; N,
18.01; S, 13.74.
3-Benzyl-4-methyl-2-(N-phenylimino)-1,3-thiazoline
White needles. m.p: 109–111 1C [Lit.22 111–113 1C].
2-(N-Benzylimino)-3-(dimethylamino)-5-methyl-1,3-thiazolidin-
4-one (4g). Solid. m.p: 87–89 1C. IR (KBr) n = 3047, 2968, 1727,
1
(3e). 1637, 1238, 761, 682 cmꢀ1; H NMR (CDCl3, 500 MHz): d 1.62
(d, 3H, J = 6.8 Hz), 2.97 (s, 6H), 3.95 (q, 1H, J = 6.8 Hz), 4.5
3-Ethyl-4-methyl-2-(N-phenylimino)-1,3-thiazoline (3f). Solid. (d, 2H, J = 4.9 Hz), 7.22–7.35 (m, 5H). 13C NMR (CDCl3, 125
m.p: 99–102 1C. 1H NMR (CDCl3, 500 MHz): d 1.33 (t, 3H, MHz): d 19.5, 39.6, 43.1, 55.9, 126.7, 127.3, 128.3, 139.1, 149.0,
J = 6.9 Hz), 2.13 (d, 3H, J = 1.0 Hz), 3.99 (q, 2H, J = 6.9 Hz), 172.8. EI-MS: m/z (relative intensity): 263(M+, 100), 219(8),
5.54 (d, 1H, J = 1.0 Hz), 7.05 (t, 1H, J = 7.3 Hz), 7.11 (d, 2H, 191(5), 172(14), 151(4), 132(18), 118(17), 117(12), 91(68),
J = 7.3 Hz), 7.33 (t, 2H, J = 7.8 Hz). 13C NMR (CDCl3, 125 MHz): d 65(21). Anal. calcd for C13H17N3OS: C, 59.29; H, 6.51; N,
13.6, 14.4, 39.6, 93.3, 121.9, 121.9, 123.3, 129.3, 135.0, 15.96; S, 12.17. Found: C, 59.26; H, 6.46; N, 15.89; S, 12.14.
150.2, 160.7. EI-MS: m/z (relative intensity): 218(M+, 100),
189(56), 150(7), 114(77), 105(33), 79(9), 77(17). Anal. calcd for
C12H14N2S: C, 66.05; H, 6.42; N, 12.84; S, 14.68. Found: C, 66.06;
4. Conclusions
H, 6.49; N, 12.71; S, 14.62.
Although numerous organic reactions (commonly acid-catalyzed)
3-Ethyl-2-(N-benzylimino)-5-methyl-4-phenyl-1,3-thiazoline (3g).
have already been described to get 2-imino-1,3-thiazolines (3) and
Solid. m.p: 155–157 1C. IR (KBr) n = 3042, 2926, 1641, 1606,
1,3-thiazolidin-4-ones (4), the importance of such heterocycles as
biologically active compounds, particularly as promising drugs
that induce apoptosis in cancer cells, deserves further synthetic
procedures to be developed. Herein a new, efficient and promising
1450, 1359, 1027, 699 cmꢀ1. 1H NMR (CDCl3, 300 MHz): d 1.09
(t, 3H, J = 6.9 Hz), 1.94 (s, 3H), 3.67 (q, 2H, J = 6.9 Hz), 4.40 (s,
2H), 7.20–7.47 (m, 10H). 13C NMR (CDCl3, 75.4 MHz): d 13.1,
13.9, 40.6, 58.5, 106.5, 126.5, 127.7, 128.3, 128.8, 128.9, 130.3,
scale-up alternative process is described by means of electro-
131.4, 135.1, 141.7, 147.1, 162.0. EI-MS: m/z (relative intensity):
chemical methodology. The cathodic generation ‘‘in situ’’ of
308(M+, 100), 280(M+ ꢀ28, 55), 253(8), 204(25), 176(30), 147(14),
active bases (EGB promoters), with adequate control of the
116(12), 105(10), 91(16), 77(6), 65(6). Anal. calcd for C19H20N2S:
amount and strength of the base, is often highly desirable in the
C, 74.03; H, 6.49; N, 9.09; S, 10.39. Found: C, 73.92; H, 6.49; N,
development of new synthetic reactions, such as the preparation
9.01; S, 10.42.
here described. Hence new derivatives of these valuable five
membered ring frameworks are now fully characterized.
3-Ethyl-5-methyl-4-phenyl-2-(N-phenylimino)-1,3-thiazoline (3h).
Solid. m.p: 109–111 1C. IR (KBr) n = 3057, 3024, 2971, 2926,
1601, 1563, 1487, 1443, 1322, 1253, 1077, 760, 699. 1H NMR
(CDCl3, 300 MHz): d 1.16 (t, 3H, J = 6.9 Hz), 1.92 (s, 3H), 3.76 (q, Conflicts of interest
1H, J = 6.9 Hz), 7.04 (t, 1H, J = 7.4 Hz), 7.10 (d, 2H, J = 7.1 Hz),
The authors declare no conflict of interest.
7.30–7.40 (m, 4H), 7.42–7.50 (m, 3H). 13C NMR (CDCl3, 75.4
MHz): d 12.9, 13.9, 40.9, 106.7, 121.9, 123.0, 128.9, 129.1, 129.6,
130.4, 134.5, 145.5, 152.3, 158.8. EI-MS: m/z (relative intensity):
Acknowledgements
294(M+, 100), 265(12), 251(14), 190(52), 147(10), 104(5), 77(4).
Anal. calcd for C18H18N2S: C, 73.47; H, 6.12; N, 9.52; S, 10.88. The authors gratefully acknowledge the financial support of the
Found: C, 73.48; H, 6.49; N, 9.79; S, 10.82.
Ministry of Higher Education and Scientific Research of Tunisia
5-Methyl-3-phenyl-2-(N-phenylimino)-1,3-thiazolidin-4-one (4a). (MHESR) through the lab LR99ES15, and the financial support
Solid. m.p: 94–96 1C [Lit.35 98–99 1C]; IR (KBr) n = 2974, 1714, of the University of Alcala- project No. CCGP2017-EXP/009.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018
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