Behavior of 2-iminothiazolidin-4-one with different reagents

Article abstract of DOI:10.1002/jhet.628

Annulations of 2-imino-4-thiazolidinone (5) via cycloaddition followed by cyclocondensation reaction with 1,3-diphenylpropenone (6), benzylidenemalonate, and 1,2-bis(chloromethyl)benzene gave 7, 19 and 20, respectively. Reaction of 5 with suitable electrophiles (Mannich bases of arylalkanone), 1,4-dichlorobenzene (diarylmethylation), and formylation afforded 8/9, 21/22, and 23, respectively.

Full text of DOI:10.1002/jhet.628

September 2011
Behavior of 2-Iminothiazolidin-4-one with Different Reagents
1169
Wafaa S. Hamama,* Mohadamed A. Ismail, Mamdoh Soliman,
Saad Shaaban, and Hanafi H. Zoorob
Chemistry Department, Faculty of Science, Mansoura University, Egypt
*E-mail: wshamama@yahoo.com
Received May 25, 2010
DOI 10.1002/jhet.628
Published online 9 June 2011 in Wiley Online Library (wileyonlinelibrary.com).
Annulations of 2-imino-4-thiazolidinone (5) via cycloaddition followed by cyclocondensation reaction
with 1,3-diphenylpropenone (6), benzylidenemalonate, and 1,2-bis(chloromethyl)benzene gave 7, 19 and
20, respectively. Reaction of 5 with suitable electrophiles (Mannich bases of arylalkanone), 1,4-dichlor-
obenzene (diarylmethylation), and formylation afforded 8/9, 21/22, and 23, respectively.
J. Heterocyclic Chem., 48, 1169 (2011).
INTRODUCTION
Furthermore, the diamidines exhibit broad spectrum
of antimicrobial activity [10]. In light of the pharmaceu-
tical importance of several fused bicyclic ring systems,
the most important are those containing a nitrogen ring-
junction, where a nitrogen is common to two rings
[11,12], such as levamisole (imidazo[2,1-b]thiazole) (4)
[12]. So, the objective of this work was directed to
annulate 2-imino-4-thiazolidinone (5) via cycloaddition
followed by cyclo-condensation reaction, as a part of
our continuing interest in the synthesis of biologically
active molecules [13–17].
The structural and therapeutic diversity coupled with
commercial viability of small heterocyclic molecules have
fascinated organic and medicinal chemists. In recent years,
4-thiazolidinones are one of the most extensively investi-
gated classes of compounds. The thiazolidinone ring sys-
tem has been widely used in the investigation of pharmaco-
logically active heterocyclic compounds [1–4], perhaps
most notably as a common structural motif in the Rosiglita-
zone class of PPAR-8 agonists 1 [5]. In contrast, the isos-
teric 2-imino-4-thiazolidinone and its tautomeric 2-amino-
4-thiazolidinone have been less investigated in the medici-
nal chemistry field, although potent anti-inflammatory Dar-
bufelone (2) [6] and antiviral activities [7] have been
found. They are less common, despite the clear opportunity
to introduce an additional handle for chemical diversity
and thus enable exploration of unmapped regions of a thia-
zolidinone-based pharmacophore (region B) 3. One reason
might be the lack of efficient synthetic methods to prepare
iminothiazolidinones, in particular with distinct substitu-
tion patterns on each of the nitrogen atoms. The amidine
moiety is found in a wide range of biologically active mol-
ecules, including various serine protease inhibitors [8] and
antiprotozoal agents [9].
RESULTS AND DISCUSSION
The 2-iminothiazolidin-4-one (5) has three active cen-
ters the amido group (N3HACO), imino group (¼¼N6H),
and the active methylene group (C5HaHb).
The molecular parameters and the electronic structure
of 2-iminothiazolidin-4-one (5) indicate that the nucleo-
philicity is decreasing in the following order amido
group (ANHACO) > imino group (¼¼NH) > active
methylene (ACH2A). The reaction between amidine
moiety as a bifunctional nucleophile with different
reagents to produce bridgehead nitrogen heterocycles of
C
V
2011 HeteroCorporation

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W. S. Hamama, M. A. Ismail, M. Soliman, S. Shaaban, and H. H. Zoorob
Vol 48
Figure 3. Structures of hydrazone derivative 16 and meso-ionic 6-ethyl-
3-phenylthiazolo[3,2-a]pyrmidine-5,7-dione (17).
have bacteriostatic and strong fungistatic action [13].
Therefore, Claisen-Schmidt condensation of 8 with two
moles of 4-methoxybenzaldehyde in ethanol catalyzed
by few drops of acetic acid gave a single isomer of the
arylidene 12. Its structure was elucidated by IR, 1H-
NMR, and mass spectra. Furthermore, it was decided to
prepare binary pyran attached 2-(methyl)imino-1,3-thia-
zolidin-4-one aiming to improve their biological po-
tency, because pyrans individually or in combination
with heterocycles possess significant biological proper-
ties [21a]. Accordingly, the reaction of 2-imino-4-thiazo-
lidinone (5) with two moles of activated cyano olefin
such as ethyl 2-cyano-3-phenylacrylate (13) catalyzed
by triethylamine afforded compound 15. The structure
of 15 is based on analytical and spectroscopic features.
A plausible mechanism for the formation of pyran deriv-
ative 15 probably involves an acyclic Michael adduct as
intermediate 14 which cyclizes via the addition of enolic
hydroxyl group to the cyano group [21b]. It is accompa-
nied with rearrangement at C-5 in the thiazole ring.
The geometry of compound 12 was established by
the quantum mechanical calculations using the PM3
semiempirical molecular orbital method. The (Z,Z) con-
figuration was found to have the lower total energy
(ꢀ6569.7 k cal/mol), (E,Z) configuration have ꢀ6568.3
k cal/mol, and the higher energy for (E,E) configura-
tion (ꢀ6565 k cal/mol) in (Z)-3-((Z)-2-benzoyl-3-(4-
methoxyphenyl)allyl)-2-imino-5-(4-methoxybenzylidene)
thiazolidin-4-one (12).
Figure 1. Thiazole derivatives reported to have pharmacological activities.
expected pharmacological activities, pursued us to syn-
thesize thiazolopyrimidines which were recently pre-
pared as patent in the literatures because of their inter-
esting biological and pharmaceutical activities [18–20].
The influence of substituents at positions 6 and 7 as
well as the substitution pattern of the two phenyl rings
in the positions 2 and 5 on activity is also reported [21].
Therefore, this study provides a suitable method for the
selective synthesis of thiazolo[3,2-a]pyrimidinone deriv-
ative 7 through the reaction of 2-imino-4-thiazolidinone
(5) with benzalacetophenone (6) in ethanol in presence
of triethylamine via cycloaddition followed by cyclocon-
densation reaction. Its constitution was supported by ele-
1
mental analysis, IR, H-NMR, and MS spectra.
Another route for synthesis of 5-arylthiazolo[3,2-a]py-
rimidine via condensation of compound 5 with suitable
electrophiles is
a straightforward and often used
approach. The substitution pattern of the annulated py-
rimidine ring formed is determined in these reactions by
the structure of the biselectorophile. Accordingly, Man-
nich bases of arylalkanone are used to afford 8 and 9,
which characterized by their spectroscopic properties
1
(IR, H-NMR, and MS) and elemental analysis. Intramo-
lecular cyclization of compound 8 to 10 between sec-
ondary amine and carbonyl group was unsuccessful.
However, N-(5-acetyl-4-oxo-3-(3-oxo-3-phenylpropyl)th-
iazolidin-2-ylidene)acetamide (11) was obtained instead
of the anticipated thiazolo[3,2-a]pyrimidinone 10. Its
Table 1
The important quantum chemical parameters for the effective atoms
and bonds in compound 5, as obtained from PM3 semiempirical MO
calculations.
1
structure was ascertained by elemental analysis, IR, H-
NMR, and mass spectra. Several arylidene derivatives
Atomic
charge
Bond
length
Bond
order
Atom
Bond
˚
N6
N3
C5
ꢀ0.077
ꢀ0.021
ꢀ0.222
N6AH(N6)
N3AH(N3)
C5AH(C5)a
C5AH(C5)b
0.9882 A
0.958
0.943
0.962
0.963
˚
0.9968 A
˚
0.1060 A
˚
0.1057 A
H(N6)
H(N3)
H(C5)a
H(C5)b
þ0.082
þ0.105
þ0.118
þ0.117
Figure 2. Synthesis of thiazolo[3,2-a]pyrimidinone derivative 7.
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Behavior of 2-Iminothiazolidin-4-one with Different Reagents
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Scheme 1. Synthesis and reactions of 2-imino-3-(3-oxo-3-phenylpropyl)thiazolidin-4-one (8).
Finally, formation of hydrazone derivative 16 was
achieved by treatment of 8 with phenylhydrazine in
alcohol catalyzed by of few drops of acetic acid. How-
ever, Glennon [22] synthesized meso-ionic 6-ethyl-3-
phenylthiazolo[3,2-a]pyrmidine-5,7-dione (17) by ther-
mal condensation of 2-methylamino-4-phenylthiazole
with bis(2,4,6-trichlorophenyl)ethyl-malonate.
There is an interest for introduction of a substituent at
C-5 of pyrimidine moiety because biological activity
enhancement of the products formed [23–25]. Therefore,
this prompted us to prepare ethyl 3,7-dioxo-5-phenyl-
3,5,6,7-tetrahydro-2H-thiazolo[3,2-a]pyrimidine-6-carbox-
ylate (18) through the cyclocondensation of 5 with benzyli-
denemalonate which is formed in situ was unsuccessful.
However, the bis fused thiazolo[3,2-a]pyrimidine 19 was
isolated as angular compound instead of 18. Compatible
analytical and spectroscopic evidences were gained for
structure of 19.
Furthermore, the interesting Psychopharmacological
activity of benzodiazepine [26,27] enthused us to synthe-
size the 5,10-dihydrobenzo[e]thiazolo[3,2-a][1,3]diazepin-
3(2H)-one (20). Compound 20 has been obtained through
cyclocondensation of 5 with 1,2-bis(chloromethyl)benzene
[28]. Formulation of structure 20 was based on elemental
analysis, IR, 1H-NMR, and MS spectra. An attempted dia-
rylmethylation of 5 with 1-chloro-4-(chloromethyl)benzene
in the presence of K2CO3/acetone in molar ratio (1:2) gave
a mixture of 21 and 22, which isolated by column chroma-
tography using ethyl acetate/petroleum ether (60–80ꢁC)
(1:4) as eluent for separating 21, whereas elution with ethyl
acetate/petroleum ether (60–80ꢁC) (2:4) gave 22 in 68%
and 29% yields, respectively. Also, when the previous
reaction was repeated in a molar ratio (1:3), compound 22
was isolated only instead of triarylmethyl derivative. The
condition of the formation of 21 and 22 was in line with
that reported in literature [29–31]. The structures of 21 and
22 were confirmed on the basis of their elemental analyses
1
and spectral data. Thus, their H-NMR spectra displayed
signals characteristic for thiazole moiety, and the signals
for benzyl moiety. In the mass spectra, the molecular ion
peaks of 21 and 22 were m/z 240 (30) and 364 (3). The ge-
ometry of compound 22 was established by the quantum
mechanical calculations using the PM3 semiempirical mo-
lecular orbital method. The (Z) configuration was found to
have the lower total energy of ꢀ4020 k cal/mol, whereas
the (E) configuration was found to have a total energy of
ꢀ3999.8 kcal/mol, respectively. This indicates the global
stability of the (Z) configuration as (Z)-3-(4-chlorobenzyl)-
2-(4-chlorobenzylimino)thiazolidin-4-one (22). Attempted
formylation of 5 via halomethyl-eniminium salt, obtained
from Vilsmeier-Haack reagent (DMF/POCl3), afforded
the 4-chloro-5-formylthiazole derivative 23, the structural
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W. S. Hamama, M. A. Ismail, M. Soliman, S. Shaaban, and H. H. Zoorob
Vol 48
ether (40–60)/ethyl acetate, (1:1)]; IR (KBr) ꢀt (cmꢀ1), 2936
(CAH, stretch), 1674 (CO), 1564 (C¼¼N), 1448 (CAC), 1266
(CAH), 768 (CAS); 1H-NMR (200 MHz, DMSO-d6): d, 3.91
(s, 2H, CH2), 5.56 (d, J ¼ 1.2 Hz, 1H, CH), 6.70 (d, J ¼ 1.2
Hz, 1H, CH), 7.43–7.63 (m, 10H, Ar-H); ms: (m/z, %): 306
(Mþ, 5), 136 (6), 134 (100). Anal. Calcd. for C18H14N2OS
(306.38): C, 70.56; H, 4.61; N, 9.14. Found: C, 70.39; H,
4.80; N, 9.10.
Scheme 2. Synthetic mechanism for the synthesis of 7-phenyl-2H-thia-
zolo[3,2-a]pyrimidine-3-one[5,6:50,60]-2H-thiazolo[3,2-a]pyrimidine-3,7-
dione (19).
2-Imino-3-(3-oxo-3-arylpropyl)thiazolidin-4-ones 8 and 9
General procedure. A mixture of 2-iminothiazolidin-4-one
(5) (0.5 g, 4.3 mmol) and 4-(3-oxo-3-phenylpropyl)morpholin-
4-ium chloride (1.1 g, 4.3 mmol) or 4-(3-oxo-3-(p-tolyl)pro-
pyl)morpholin-4-ium chloride (1.16 g, 4.3 mmol) in ethanol
(10 mL) was dissolved in least amount of water. The reaction
mixture was refluxed on a steam bath for 8 h, then kept over-
night at room temperature. The formed precipitate was filtered,
dried, and recrystallized from ethanol to afford the desired imi-
nothiazolidin-4-one derivatives 8 and 9, respectively.
2-Imino-3-(3-oxo-3-phenylpropyl)thiazolidin-4-one (8). (0.86
g, 81%); mp 181–182ꢁC; Rf ¼ 0.46 [pet. ether (40–60)/ethyl
acetate, (1:2)]; white crystals; IR (KBr) ꢀt(cmꢀ1), 3178 (NH),
3060 (CAH), 2918 (CAH, stretch), 1715, 1682 (2CO), 1452,
1352 (CAH), 1254, 1206 (CAN), 744 (CAS); 1H-NMR (200
MHz, DMSO-d6): d, 3.35 (t, 2H overlapped with water of
DMSO), 3.72 (t, J ¼ 7.2 Hz, 2H, CH2), 3.93 (s, 2H, CH2),
7.51–8.01 (m, 5H, Ar-H), 9.30 (s, 1H, NH exchangeable with
D2O); ms: (m/z, %): 248 (Mþ, 3), 143 (78), 105 (97), 77
(100). Anal. Calcd. for C12H12N2O2S (248.3): C, 58.05; H,
4.87; N, 11.28. Found: C, 58.24; H, 4.79; N, 11.25.
formula of 23 was asserted by spectral data. While formy-
lation of thiazolidinone with different reagents such
as t-butoxy-bis(dimethylamino)methane [Bredereck’s rea-
gent] in dimethylformamide was reported in the literature
as patent [32,33].
(Z)-2-Imino-3-(3-oxo-3-(p-tolyl)propyl)thiazolidin-4-one (9). (0.99
g, 88%); mp 200–202ꢁC; white crystals; Rf ¼ 0.49 [pet. ether
(40–60)/ethyl acetate, (1:2)]; IR (KBr) ꢀt (cmꢀ1), 3178 (NH),
3060 (CAH), 2918 (CAH, stretch), 1715, 1682 (2CO), 1452,
1352 (CAH), 1254, 1206 (CAN), 744 (CAS); 1H-NMR (300
MHz, DMSO-d6): d, 2.36 (s, 3H, CH3), 3.29 (t, J ¼ 7.2 Hz,
2H, CH2), 3.66 (t, J ¼ 7.2 Hz, 2H, CH2), 3.90 (s, 2H, CH2),
7.31–7.80 (m, 4H, Ar-H), 9.27 (s, 1H, NH); ms: (m/z, %): 262
(Mþ, 18), 261 (100), 260 (63). Anal. Calcd. for C13H14N2O2S
(262.33): C, 59.52; H, 5.38; N, 10.68. Found: C, 59.39; H,
5.59; N, 10.61.
EXPERIMENTAL
All melting points (uncorrected) were determined on a Gal-
lenkamp electric melting point apparatus. Elemental microanaly-
ses were carried out at Microanalytical Unit (Faculty of Science,
Cairo University). The Infrared spectra were measured on a
1
Mattson 5000 FTIR spectrometer. H-NMR data were measured
in CDCl3 and DMSO solution on a Varian XL 200, 300 MHz
instruments using TMS as internal standard. Chemical shifts
were reported in ppm (d) downfield from internal TMS. Mass
spectra were recorded on GC-MS QP-1000 EX (EI, 70 ev), Shi-
madzu Instrument. Reactions were monitored by thin layer chro-
matography (TLC) using EM science silica gel coated plates
with visualization by irradiation with ultraviolet lamp. Molecu-
lar Orbital Calculations and the quantum chemical parameters
were determined using the PM3-Semi-empirical method using
evaluation copy of HyperChem.ver 7.5 (www.hyper.com). Pack-
age accommodated on PIV-2.8 MHz computer system. The mo-
lecular quantum parameters and the electronic structure (Molec-
ular Orbital Calculations) and the quantum chemical parameters
were determined using the PM3-Semi-empirical MO method
using evaluation copy of Hyper Chem. Ver. 7.5 (www.hyper.
com). Package (accommodated on PIV-2.8 MHz Computer Sys-
tem) of this compound were calculated.
Scheme 3. Reactions of 2-iminothiazolidin-4-one (5) with various
chloromethane derivatives and its formylation.
5,7-Diphenyl-2H-thiazolo[3,2-a]pyrimidin-3(5H)-one (7). A
mixture of 2-iminothiazolidin-4-one (5) [34] (0.5 g, 4.3 mmol)
and benzalacetophenone (6) (0.9 g, 4.3 mmol) in ethanol (10
mL) and few drops of triethylamine was refluxed for 8 h on a
steam bath, and left to cool. The formed precipitate was fil-
tered, dried, and recrystallized from ethanol to afford (0.99 g,
75%) of 7; mp 160–162ꢁC; yellow crystals; Rf ¼ 0.58 [pet.
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Behavior of 2-Iminothiazolidin-4-one with Different Reagents
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(Mþ, 5), 223 (17), 222 (100), 221 (58), 76 (49). Anal. Calcd.
for C18H18N4OS (338.43): C, 63.88; H, 5.36; N, 16.56. Found:
C, 63.67; H, 5.51; N, 16.48.
(Z)-N-(5-Acetyl-4-oxo-3-(3-oxo-3-phenylpropyl)thiazolidin-
2-ylidene)acetamide (11). A solution of 2-imino-3-(3-oxo-3-
phenylpropyl)thiazolidin-4-one (8) (0.5 g, 2.01 mmol) in acetic
anhydride (5 mL) was heated on a steam bath for 30 min, then
kept overnight at room temperature, and poured into ice water;
the formed precipitate after 15 min was filtered, dried, and
then purified by crystallization from ethanol to afford (0.64 g,
96%) of 11; mp 142–144ꢁC; yellow crystals; Rf ¼ 0.63 [pet.
ether (40–60)/ethyl acetate, (1:1)]; IR (KBr) ꢀt (cmꢀ1), 2923
(CAH, stretch), 1754, 1677 (CO), 1594 (CAC, stretch), 1518
(C¼¼N), 1216, 1127 (CAN, stretch), 895, 745 (CAS); 1H-
NMR (200 MHz, DMSO-d6): d, 2.23(s, 3H, CH3), 2.45(s, 3H,
CH3), 3.56 (t, J ¼ 7.2 Hz, 2H, CH2), 4.39 (t, J ¼ 7.2 Hz, 2H,
CH2) 6.79 (s, 1H, CH), 7.49–7.67 (m, 3H, Ar-H), 7.98 (d, J ¼
7.5 Hz, 2H, Ar-H); ms: (m/z, %): 332 (Mþ, 6), 290 (33), 248
(40), 158 (10), 143 (15), 133 (80), 105 (100), 77 (99). Anal.
Calcd. for C16H16N2O4S (332.37): C, 57.82; H, 4.85; N, 8.43.
Found: C, 57.69; H, 5.12; N, 8.33.
(Z)-3-((Z)-2-Benzoyl-3-(4-methoxyphenyl)allyl)-2-imino-5-
(4-methoxybenzylidene)thia-zolidin-4-one (12). A mixture of
8 (0.5 g, 2.01 mmol) and 4-methoxybenzaldehyde (0.55 g,
4.02 mmol) in acetic acid (5 mL) refluxed for 3 h, kept over-
night at room temperature, and diluted with water. The formed
precipitate was filtered, dried, and then purified by recrystalli-
zation from ethanol to afford (0.63 g, 65%) of 12; mp 121–
122ꢁC; red crystals; Rf ¼ 0.66 [pet. ether (40–60)/ethyl ace-
tate, (3:2)]; IR (KBr) ꢀt (cmꢀ1), 2766 (CAH, stretch), 1686,
1594 (2CO), 1502 (C¼¼N), 1362, 1258 (CAH), 750 (CAS);
1H-NMR (200 MHz, DMSO-d6): d, 3.32 (s, 2H, CH2), 3.79 (s,
6H, 2OCH3), 7.05–7.08 (m, 8H, Ar-H), 7.48–7.67 (m, 5H, Ar-
H), 7.97 (s, 1H, CH), 8.00 (s, 1H, CH), 9.68 (s, 1H, NH); ms:
(m/z, %): 484 (Mþ, 5), 234 (33), 164 (100), 120 (29), 77 (25).
Anal. Calcd. for C28H24N2O4S (484.57): C, 69.40; H, 4.99; N,
5.78. Found: C, 69.22; H, 5.21; N, 5.61.
(Z)-Ethyl 2-amino-5-((5-benzylidene-2-imino-4-oxothiazoli-
din-3-yl)methyl)-4,6-diphenyl-4H-pyran-3-carboxylate (15). A
mixture of 8 (0.499 g, 2.01 mmol) and ethyl 2-cyano-3-phenyla-
crylate (0.81 g, 4.02 mmol) in ethanol (10 mL) and few drops of
triethylamine was refluxed for 6 h on a steam bath. The formed
precipitate was filtered, dried, and then purified by crystalliza-
tion from ethanol to afford (0.62 g, 57%) of 15; mp 164–165ꢁC;
yellow crystals; Rf ¼ 0.49 [pet. ether (40–60)/ethyl acetate,
(1:3)]; IR (KBr) ꢀt(cmꢀ1), 3818, 3746 (NH2), 3418 (NH), 1666
(CO), 1636 (CO), 1540 (C¼¼N), 1272 (CAO), 680 (CAS); ms:
(m/z, %): 537 (Mþ, 8), 204 (17), 134 (100), 105 (28), 77 (51).
Anal. Calcd. for C31H27N3O4S (537.63): C, 69.25; H, 5.06; N,
7.82. Found: C, 69.49; H, 5.31; N, 7.74.
2-Imino-3-(3-phenyl-3-(2-phenylhydrazono)propyl)thiazo-
lidin-4-one (16). A mixture of 8 (0.5 g, 2.01 mmol) and phe-
nyl hydrazine (0.22 g, 2.01 mmol) in acetic acid (5 mL) was
heated for 6 h on a steam bath, stand overnight at room tem-
perature, diluted with ice water and basified with Na2CO3 so-
lution. The formed precipitate was filtered, dried, and then
purified by crystallization from ethanol to afford (0.3 g, 44%)
of 16; mp 221–222ꢁC; reddish brown powder; Rf ¼ 0.56 [pet.
ether (40–60)/ethyl acetate, (1:3)]; IR (KBr) ꢀt (cmꢀ1), 3734,
3222 (NH), 2996 (CAH, stretch), 1684 (CO), 1570 (C¼¼N),
1508 (C¼¼N), 1254 (CAH), 754, 692 (CAS); 1H-NMR (300
MHz, DMSO-d6): d, 3.32 (t, J ¼ 6.9 Hz, 2H, CH2), 3.49 (t,
6.9 Hz, 2H, CH2), 4.00 (s, 2H, CH2), 7.19–7.47 (m, 10H, Ar-
H), 9.60 (s, 1H, ¼¼NH), 9.77 (s, 1H, NH); ms: (m/z, %): 338
7-Phenyl-2H-thiazolo[3,2-a]pyrimidine-3-one[5,6:50,60]-2H-
thiazolo[30,20-a]pyrimidine-30,70-dione (19). A mixture of 5 (1.0
g, 8.6 mmol), diethyl malonate (0.69 g, 4.3 mmol), and benzaldhyde
(0.46 g, 4.3 mmol) or diethyl 2-benzylidenemalonate (1.07 g, 4.3
mmol) in ethanol (10 mL) was refluxed on steam bath for 6 h, and
then left to cool. The formed precipitate was filtered, dried, and
recrystallized from ethanol to afford (0.48 g, 30%) of 19; mp 199–
201ꢁC; yellow crystals; Rf ¼ 0.64 [pet. ether (40–60)/ethyl acetate,
(1:2)]; IR (KBr) ꢀt (cmꢀ1), 3131 (CAH, stretch), 3044 (CAH,
1
stretch), 1738, 1657 (CO), 1341 (CH), 1163 (CAN, stretch); H-
NMR (300 MHz, DMSO-d6): d, 3.53 (s, 4H, 2CH2), 5.56 (d, 1H,
CH), 7.30–7.51 (m, 5H, Ar-H); ms: (m/z, %): 368 (Mþꢀ2, 5), 133
(11), 134 (100). Anal. Calcd. for C16H10N4O3S2 (370.41): C, 51.88;
H, 2.72; N, 15.13. Found: C, 51.72; H, 2.98; N, 15.00.
5,10-Dihydrobenzo[e]thiazolo[3,2-a][1,3]diazepin-3(2H)-one
(20). A mixture of 1,2-bis(chloromethyl)benzene (0.75 g, 4.3
mmol) and 5 (0.5 g, 4.3 mmol) were fused in an oil bath at 290ꢁC
for about 1.5 h, then ethanol was added. The formed precipitate
was filtered, dried, and crystallized from DMF to afford (0.88 g,
94%) of 20; mp > 300ꢁC; yellow crystals; Rf ¼ 0.59 [pet. ether
(40–60)/ethyl acetate; (1:2)]; IR (KBr) ꢀt (cmꢀ1), 2900 (CAH,
stretch), 3000 (CAH, stretch), 1676 (CO), 1548 (C¼¼N), 1408
1
(CAC stretch), 1158 (CAN, stretch), 750 (CAS); H-NMR (300
MHz, DMSO-d6): d, 4.04 (s, 6H, 3CH2), 7.11–7.46 (m, 4H, Ar-
H); ms: (m/z, %): 218 (Mþ, 50), 135 (50), 117 (100), 105 (30).
Anal. Calcd. for C11H10N2OS (218.27): C, 60.53; H, 4.62; N,
12.83. Found: C, 60.18; H, 4.32; N, 12.78.
3-(4-Chlorobenzyl)-2-[(imino) and (4-chlorobenzylimi-
no)]thiazolidin-4-ones 21 and 22. A mixture of 1-chloro-4-
(chloromethyl)benzene (1.38 g, 8.6 mmol), 2-iminothiazolidin-
4-one (5) (0.5 g, 4.3 mmol), potassium carbonate (1 g, 8 mmol),
and acetone (10 mL) was refluxed for 6 h on a steam bath; the
reaction mixture was poured onto ice water, and the formed pre-
cipitate was filtered, dried, and purified by column chromatogra-
phy using [(ethyl acetate/pet. ether) (60–80) (1:4)] as eluent for
separating 21 in (29%) yield, whereas, using ethyl acetate/pet.
ether (60–80ꢁC) (2:4) as eluent for separating 22 in (64%) yield.
Moreover, when the previous reaction of 2-iminothiazolidin-
4-one (5) (0.499 g, 4.3 mmol) with 1-chloro-4-(chloromethyl)-
benzene (2.08 g, 12.9 mmol) in the presence of K2CO3 (1.5 g,
12.9 mmol) and by using the same reaction conditions only
compound 22 was isolated.
3-(4-Chlorobenzyl)-2-iminothiazolidin-4-one (21). (0.3 g,
29%); mp 142–143ꢁC; yellow crystals; Rf ¼ 0.52 [pet. ether
(40–60)/ethyl acetate, (1:2)]; IR (KBr) ꢀt (cmꢀ1), 3178 (NH),
2786 (CAH, stretch), 1696 (CO), 1622 (C¼¼N), 1474 (C¼¼C),
1432 (CH), 1212 (CAN, stretch), 800 (CACl); 1H-NMR
(DMSO-d6): d, 3.9 (s, 2H, CH2), 4.6 (s, 2H, CH2), 7.2–7.4 (m,
4H, Ar-H), 9.81 (s, 1H, NH); ms: (m/z, %): 240 (Mþ, 30), 242
(10), 205 (29), 126 (37), 125 (100). Anal. Calcd. for
C10H9ClN2OS (240.71): C, 49.90; H, 3.77; N, 11.64. Found:
C, 49.51; H, 3.47; N, 11.57.
3-(4-Chlorobenzyl)-2-(4-chlorobenzylimino)thiazolidin-4-one
(22). (1.01 g, 64%); mp 166–168ꢁC; brown crystals; Rf ¼ 0.61
[pet. ether (40–60)/ethyl acetate, (1:2)]; IR (KBr) ꢀt(cmꢀ1), 1690
(CO), 1538 (C¼¼N), 1288 (CH), 1090 (CAN, stretch), 802
1
(CACl); H-NMR (300 MHz, DMSO-d6): d, 4.09 (s, 2H, CH2),
4.6 (s, 4H, 2CH2), 7.27–7.43 (m, 8H, Ar-H); ms: (m/z, %): 364
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1174
W. S. Hamama, M. A. Ismail, M. Soliman, S. Shaaban, and H. H. Zoorob
Vol 48
(Mþꢀ1, 3), 366 (0.96), 368 (0.31), 241 (29), 239 (73), 211 (13),
125 (100), 77 (4). Anal. Calcd. for C17H14Cl2N2OS (365.28): C,
55.90; H, 3.86; N, 7.67. Found: C, 55.72; H, 3.56, N 7.57.
[13] Hamama, W. S.; Abd El-Magid, O. M.; Zoorob, H. H. Z
Naturtorsch 2006, 61b, 1.
[14] Zoorob, H. H.; Hamama, W. S.; Abd El-Magid, O. M.;
Soliman, M. S. J Chem Res 2005, 10, 669.
N0-(4-Chloro-5-formylthiazol-2-yl)-N,N-dimethylformimida-
mide (23). A mixture of 2-iminothiazolidin-4-one (5) (1.0 g, 8.6
mmol) in DMF (5 mL) then POCl3 (4 mL) was added in portion
while stirring in ice bath for 45 min. Then, the reaction mixture
heated on water bath (60ꢁC) for 30 min then poured on ice and
basified with NaHCO3. The formed precipitate was filtered, dried,
and purified by crystallization from ethanol to afford (1.68 g,
90%) of 23; mp 132–133ꢁC; yellow crystals; Rf ¼ 0.68 [pet. ether
(40–60)/ethyl acetate, (1:3)]; IR (KBr) ꢀt(cmꢀ1), 1636 (CO), 1468
(CH), 1400 (CAC), 1236, 1128 (CAN, stretch), 800 (CACl); 1H-
NMR (300 MHz, DMSO-d6): d, 3.06 (s, 3H, CH3), 3.21 (s, 3H,
CH3), 8.53 (s, 1H, CH), 9.75 (s, 1H, CH); ms: (m/z, %): 217 (Mþ,
98), 219 (32), 83 (100). Anal. Calcd. for C7H8ClN3OS (217.68):
C, 38.62; H, 3.70; N, 19.30. Found: C, 38.48; H, 3.59; N, 19.24.
[15] Hamama, W. S. Synth Commun 2001, 31, 59.
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Ismail, M. A. Tetrahedron 1996, 52, 10147.
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Konno, Jpn Korai Tokyo Koho JPN07,165,748, 1995; C A 1996, 124,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet