Synthesis and biological evaluation of some new Thiazolo[3,2-a][1,3,5] triazine derivatives

Article abstract of DOI:10.1007/s00044-011-9783-1

2-Iminothiazolidin-4-one (1) was utilized for the synthesis of several new thiazolo[3,2-a][1,3,5]triazine derivatives. 3-Phenyl-3,4-dihydro-2H-thiazolo[3, 2-a][1,3,5] triazin-6(7H)-one (2) was prepared according to Mannich procedure. Both compounds 1 and 2 reacted with aromatic aldehydes to afford arylidene derivatives 3-7. Compounds 5-7 were obtained through another two routes of preparation, first when applying Mannich reaction to compounds 3 and 4 and second by reacting compounds 2 with activated olefins 11 catalyzed by triethylamine, also, the reaction of 2 with bis arylidene 16 afforded compound 18. Compound 2 reacted with both mono and di-aromatic diazonium salts to furnish 2-aryl-azothiazolo[3,2-a]triazines 20 and 21 or bis[2-azothiazolo[3,2-a] triazine]phenylene 22, respectively. Thiocarbamoyl derivatives 25 and 26 were prepared through the reaction of active methylene and imino group in 1 with phenylisothiocyanate and carbon disulfide, respectively. Structures confirmation, geometry, and biological evaluation were applied for the newly prepared compounds. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9783-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2615–2623
DOI 10.1007/s00044-011-9783-1
ORIGINAL RESEARCH
Synthesis and biological evaluation of some new
Thiazolo[3,2-a][1,3,5]triazine derivatives
•
Wafaa S. Hamama Mohamed A. Ismail
•
•
Saad Shaaban Hanafi H. Zoorob
Received: 19 September 2010 / Accepted: 13 August 2011 / Published online: 8 September 2011
Ó Springer Science+Business Media, LLC 2011
Abstract 2-Iminothiazolidin-4-one (1) was utilized for
the synthesis of several new thiazolo[3,2-a][1,3,5]triazine
derivatives. 3-Phenyl-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]
triazin-6(7H)-one (2) was prepared according to Mannich
procedure. Both compounds 1 and 2 reacted with aromatic
aldehydes to afford arylidene derivatives 3–7. Compounds
5–7 were obtained through another two routes of prepara-
tion, first when applying Mannich reaction to compounds 3
and 4 and second by reacting compounds 2 with activated
olefins 11 catalyzed by triethylamine, also, the reaction of 2
with bis arylidene 16 afforded compound 18. Compound 2
reacted with both mono and di-aromatic diazonium salts to
furnish 2-aryl-azothiazolo[3,2-a]triazines 20 and 21 or
bis[2-azothiazolo[3,2-a]triazine]phenylene 22, respectively.
Thiocarbamoyl derivatives 25 and 26 were prepared through
the reaction of active methylene and imino group in 1 with
phenylisothiocyanate and carbon disulfide, respectively.
Structures confirmation, geometry, and biological evaluation
were applied for the newly prepared compounds.
structural similarity to purine and pyrimidine. Three iso-
mers of triazine are present and could be distinguished
from each other by the positions of their nitrogen atoms,
namely; 1,2,3-triazine, 1,2,4-triazine, and symmetrical
1,3,5-triazine (S-triazine). The later is of special interest
due to its synthetic accessibility and potential therapeutic
value as anticancer (Labouta et al., 2011), antibacterial
(Mulwad and Chaskar, 2006), antimalarial (Kusch et al.,
2011), antitubercular (Kamdar et al., 2010), antiprotozoal
(Zhou et al., 1996), and antifungal agents (Saeed et al.,
2010).
Furthermore, the S-triazine ring is a component of sev-
eral widely used industrial and agricultural chemicals as it
is used as pesticides, dyestuffs, optical bleaches, explo-
sives, and surface active agents (Freeman and Esancy,
1991; Smolin and Rapopret, 1954).
Moreover, the chemistry of this group of compounds has
been studied intensively and was the subject of many
reviews (Sathiakumar et al., 2011; Dolzhenko, 2011).
Fused thiazolo-S-triazines have been found to possess
antifolate activity (Dolzhenko and Chui, 2006; Toyoda
et al., 1997) and have been developed also as anticancer,
antibacterial, antifungal, and antiparasitic agents (Chan and
Anderson, 2006; Kompis et al., 2005; Gangjee et al.,
2007). Thiazoles are important class of heterocyclic com-
pounds in which they found in many potent biologically
active molecules such as Tiazofurin (antineoplastic drug),
Ritonavir (antiretroviral drug), Abafungin (antifungal
drug), and Sulfathiazol (antimicrobial drug). It has been
noticed continuously over the years that interesting bio-
logical activities were associated with thiazole moiety
incorporation (Wang et al., 2010).
Keywords Thiazolo[3,2-a][1,3,5]triazine ꢀ
Claisen-Schmidt condensation ꢀ Mannich reaction ꢀ
Antibacterial and antitumor evaluation
Introduction
The triazine frameworks have been shown to form a very
effective scaffold due to their ease of manipulation and
W. S. Hamama (&) ꢀ M. A. Ismail ꢀ S. Shaaban ꢀ H. H. Zoorob
Department of Chemistry, Faculty of Science, Mansoura
University, Mansoura 35516, Egypt
Within this context, and in continuation of work on S-
triazine and their derivatives, we herein, report the reac-
tions of thiazolo[3,2-a][1,3,5]triazine 2 and its precursor
e-mail: wshamama@yahoo.com
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Med Chem Res (2012) 21:2615–2623
2-Iminothiazolidin-4-one (1) for the constructions of novel
heterocyclic compounds of expected antibacterial and
antitumor activities.
in quite high yield instead of the anticipated compounds 8–
10. The proposed mechanism for this reaction includes the
liberation of the active methylene compounds which may
act as catalysts in this reaction.
This study has focused on the reaction of 1 with
aldimine as a route to obtain thiazolo[3,2-a][1,3,5]triazine
with different substitution at C-5 and C-7. Surprisingly,
treatment of 1 with N-benzylideneaniline or N-(4-meth-
ylbenzylidene)aniline afforded 3 and 4, respectively, in lieu
of 12 or 13. The structures 3 and 4 were proved on the basis
of their identical melting points with that reported in the
literature (Zoorob et al., 1997, 2001) (Schemes 1, 2).
The geometry of compounds 5–7 were studied by the
quantum mechanical calculations using the PM3 semi-
empirical molecular orbital method. The Z configuration
was found to have the lower total energy; this indicates the
global stability of the Z configuration (Figs. 1, 2).
Results and discussion
The synthetic procedures are depicted in Schemes 1, 2, 3,
4, 5. Although thiazolo[3,2-a][1,3,5]triazinone 2 has been
synthesized 30 years ago (Solov’eva-Yavits et al., 1981),
relatively less attention has been devoted for its utilization
for the synthesis of relative new heterocyclic derivatives.
2-Iminothiazolidin-4-one (1) (Moghaddam and Hojabri,
2007) is a very weak acid with a pka value in water of 11.7
(Ramsh et al., 1978). For this reason, the former ring
nitrogen atoms (both exocyclic and endocyclic) are easily
undergo amino methylation when subjected to Mannich
reaction. Therefore, compound 2 was prepared via the
reaction of 1 with formalin and aniline in a molar ratio
(1:2:1).
A considerable number of bis-heterocyclic compounds
in the literature exhibited various biological activities
including antibacterial, fungicidal, tuberculostatic, and
plant growth regulative properties (Shiba et al., 1997).
Indeed, it has been reported that, bis-heterocyclic com-
pounds display much better antibacterial activity than the
mono heterocyclic ring compounds (Kalkhambkar et al.,
2009). These observations motivated us to synthesize the
bis-1,4-(thiazolo[3,2-a][1,3,5]triazine)benzene derivative
18 (Scheme 3). The later was synthesized either by the
reaction of 2 with terphthaladelyde in a molar ratio (2:1) in
methanol in the presence of triethylamine, or by reacting 2
with activated olefins 16 (prepared in situ) which give
better yield (83%) as introduced before. The constitution of
18 was confirmed by elemental analysis and mass spectrum
which showed the molecular ion peak at m/z 564 (M?,
10%).
Several arylidene derivatives have bacteriostatic as well
as strong fungistatic action (Hamama et al., 2006). Con-
sequently, compounds 5–7 were synthesized by Claisen-
Schmidt condensation of 2 with the appropriate aldehydes
namely; benzaldehyde, piperonal, and 4-chlorobenzalde-
hyde in the presence of piperidine gave a single isomer of
the corresponding (E) or (Z)-7-arylidines 5–7. Unfortu-
nately, the yield obtained by this method was quite low, in
which the compounds were isolated in 27, 35, and 40%
yield, respectively.
The structure of compounds 5–7 were confirmed by the
1H NMR spectra which showed the olefinic protons at d
7.63 ppm and lowering of stretching frequency of the
(C=O) in the IR spectra from m 1704 to 1671 cm-1 due to
formation of a,b-unsaturated ketenes (C=C–C=O). Com-
pound 7 showed three singlet signal at d 5.05, 5.39, and
6.11 ppm corresponding to (CH2–N–) (CH2=N) and (O–
CH2–O), respectively, two multiplet signals at d 6.97–7.14
and 7.26–7.30 ppm corresponding to C6H5 and C6H3,
respectively, and (CH=Ph) appeared as a singlet signal at d
7.63 ppm. In addition, its mass spectrum showed the
molecular ion peak at m/z 365 (M?, 19%).
The geometry of 18 was studied by the quantum
mechanical calculations using the PM3 semi-empirical
molecular orbital method (Figs. 3, 4). The (Z) configura-
tion was found to have the lower total energy
(-7187.1 kcal/mol) and (-7189.1 kcal/mol), where as the
(E) configuration was found to have a total energy of
(-7189.1 kcal/mol) and (-7131 kcal/mol), respectively,
this indicate the configuration (7Z,70E)-7,70-(1,4-phenyl-
enebis(methane-1-yl-1-ylidene))bis(3-phenyl-3,4-dihydro-2H-
thiazolo[3,2-a] [1,3,5]triazin-6(7H)-one) (18) (Figs. 5, 6).
Furthermore, N,N-dimethylenamine 19 was used as
masked acyl function which obtained by reacting 2 with
dimethylformamide-dimethylacetal (DMF-DMA) (Lin and
Lang, 1980; Selic and Stanovnik, 2001). The structure 19
was supported by elemental analysis, IR, 1H NMR, and MS
In our several attempts to increase the yield of the
arylidene derivatives, compound 5 was synthesized by
another route via reacting 5-benzylidene-2-iminothiazoli-
din-4-one (3) with formalin and aniline in a molar ratio
(1:2:1). The obtained yield by this method increased but
still, from a chemical point of view, low (56% in case of
compound 5).
1
Triazolo[3,2-a]thiazolo[4,5-b]pyran derivatives 8–10
were synthesized using activated olefins 11 or via one-pot
reaction of aromatic aldehydes with active methylene
compounds. Interestingly, compounds 5–7 were obtained
spectra. The H NMR spectrum showed three singlet sig-
nals at d 3.04, 4.92, and 5.23 ppm corresponding to (N-
(CH3)2) (CH2N-) and (CH2N=) protons, respectively, two
multiplet signals at d 6.92–7.06 and 7.25–7.30 ppm
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Med Chem Res (2012) 21:2615–2623
2617
NH2
N
Ph
HN
CN
X
O
Ar
H
H
O
O
Ph
N
R
X
Ph
N
N
2 CH2O / PhNH2
( 1:2:1 )
N
N
11
S
S
N
2
S
N
1
8, Ar= C6H5; X= COOEt
9, Ar= 3,4-OCH2CH2OC6H3; X= CN
10, Ar= 4-Cl-C6H4; X= COOEt
ArCHO
ArCHO
O
H
N
Ph
N
O
2 CH2O / PhNH2
( 1:2:1 )
N
HN
S
Ar
N
S
5, Ar = C6H5
6, Ar = 3,4-OCH2OC6H3
7, Ar = C6H4Cl
Ar
3, Ar = C6H5
4, Ar = 4-CH3C6H4
Ph
R
NH
O
O
CH2O
N
N
N
S
R
S
HN
12, R= H; 13, R= CH3
Ph
N
14, R= H; 15, R= CH3
Scheme 1 Synthetic routes for the preparation of (Z)-7-Arylidene-3-phenyl-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazin-6(7H)-ones 5–7 via
Claisen-Schmidt condensation
Scheme 2 Mechanism of
OH
O
OH
formation of (Z)-7-Benzylidene-
3-phenyl-3,4-dihydro-2H-
thiazolo[3,2-a][1,3,5]triazin-
6(7H)-one (5)
Ph
Ph
Ph
N
N
Et3N
N
N
N
N
S
N
S
S
N
N
2
H
O
CN
COOC2H5
CN
COOC2H5
O
CN
Ph
Ph
-
N
N
Ph
N
N
COOEt
S
Ph
S
Ph
N
N
5
Fig. 1 Optimum geometry of compound 5
corresponding to three and two aromatic protons, respec-
tively, and a singlet signal at d 7.46 ppm for (CH=) proton.
In addition, thiazolo[3,2-a][1,3,5]triazine 2 undergoes
coupling reactions when treated with mono aromatic dia-
zonium salts or diaromatic diazonium salts to give the
corresponding 2-aryl-azothiazolo[3,2-a]triazines 20 and 21
Fig. 2 Potential energy curve of compound 5
123

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Med Chem Res (2012) 21:2615–2623
Scheme 3 Synthesis of
(7Z,70E)-7,70-(1,4-phenylenebis
(methane-1-yl-1-ylidene))
bis(3-phenyl-3,4-dihydro-2H-
thiazolo[3,2-a][1,3,5]triazin-6
(7H)-one) (18)
NH2
CN
O
N
S
N Ph
N
N
Ph N
S
N
O
NC
17
NH2
O
Ph
N
2
NC
NC
CN
O
C C
H
C C
H
N
CN
(2:1)
N
N
16
S
S
Ph N
N
or
OHC
CHO +
18
CN
(2:1:2)
CN
Fig. 3 Optimum geometry of compound 18
Fig. 6 Potential energy curve of compound 18
or bis[2-azothiazolo[3,2-a]triazine]phenylene 22, respec-
tively. Compatible analytical and spectroscopic evidences
were gained for structures of compounds 20–22. Accord-
1
ingly, the H NMR spectrum of 21 displayed three singlet
signals at d 2.23, 5.04, and 5.33 ppm corresponding to
(CH3-Ph) (CH2-N-) and (CH2-N=) protons, respectively,
two multiplet signals at d 6.94–7.10 and 7.27–7.3 ppm
for seven, two aromatic protons and singlet protons for
(S–C=N–NH). The mass spectra of 20–22 gave an addi-
tional confirmation for the structure elucidation which
showed the molecular ion peaks at m/z 337 (M?), 352
(M??1), and 580 (M? –[OH]), respectively (Scheme 4).
The formation of 20–22 was in line with that reported
previously in the literature by Sherif et al., 1993, for
coupling of arylstyryl thiazolo[3,2-a]pyrimidine. The
geometry of 20 and 21 were studied using the quantum
mechanical calculations using the PM3 semi-empirical
Fig. 4 Potential energy curve of compound 18
Fig. 5 Optimum geometry of compound 18
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Med Chem Res (2012) 21:2615–2623
2619
Scheme 4 Reactions of
thiazolo[3,2-a][1,3,5]triazinone
2 with 3ry and quaternary
amines
O
Ph
DMF-DMA
DMF
N
N
S
N
N
19
O
O
Ph
R
N N Cl
HN
N
R
Ph
N
N
N
N
S
S
N
N
20, R= H
2
21, R= CH3
Ph
N
Ph
N
N
N
O
N
S
Cl
Cl
N
N N
N N
S
H
H
N N
N N
O
22
molecular orbital method (Fig. 7). The trans (E) configu-
ration was found to have the lower total energy as the cis
(Z) configuration. This indicates the configuration (7E,70Z)-
7,70-(2,20-(1,4-phenylene)bis(hydrazin-2-yl-1-ylidene))bis(3-
phenyl-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazin-6(7H)-one)
(22) (Fig. 8).
afforded 25 in lieu of 23. The assigned structure was
established by its elemental analysis, IR, and mass spectra.
Finally, the reaction of 1 with carbon disulfide afforded
compound 26 (Scheme 5). The structure 26 was confirmed
on the basis of elemental analysis and spectral data. Thus,
1
the H NMR spectra displayed signals characteristic for
Once more, the synthesis of thiazolo[3,2-a][1,3,5]tri-
azine-7-thione derivative 24 was achieved by the reaction
of 1 with phenylisothiocyanate. Unexpectedly, the reaction
thiazole moiety. Its mass spectrum showed the molecular
ion peak at m/z 309 (M?–CH3, 8.0%).
Biological activity
Antibacterial activity
The results of antibacterial activities of some selected
compounds are shown in Table 1. Compounds were tested
at concentration level of 100 ppm. It should be mentioned
that both DMF and DMSO did not show any inhibition on
bacterial growth of the Escherichia coli. Based on the
diameter of inhibition zones, Ampicillin is used as reference
drug. Compounds 2 and 19 are more potent than Ampicillin,
while the rest of compounds showed lower activities. The
antibacterial activity of the tested compounds on the growth
of E. Coli can be ranked as descending as follow
2 = 19 > 3 > 1 = 4 = 6 = 7 = 18 = 26 > 21. These find-
ings may suggest the possible use of the compounds that
showed antibacterial activity in the field of chemotherapy as
antimicrobial agents.
Fig. 7 Optimum geometry of compound 21
Antitumor activity
The standard method used to separate, identify, and purify
DNA fragments is electrophoresis through agarose gels
Fig. 8 Potential energy curve of compound 21
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Med Chem Res (2012) 21:2615–2623
Scheme 5 Reactions of
2-iminothiazolidin-4-one (1)
with sulfur compounds
Ph
S
NH
HN
O
O
Ph
N
N
PhNCS
PhNCS
CH2O
N
S
S
S
N
23
24
S
O
O
H
N
Ph N
H
N
N
HN
Ph
S
S
HN
N
S
S
S
Ph NH
25
1
O
S
SCH3
CS2
S
S
S
NaOH, (CH3)2SO4
N
26
Table 1 Diameter of
Experimental
Compound no.
Inhibition
zone (mm)
Escherichia
coli
inhibition zone in mm as a
criterion of antibacterial activity
of some synthesized compounds
at concentration 100 ppm
All melting points were determined on a Gallenkamp
electric melting point apparatus. Elemental microanalyses
were carried out at Microanalytical Unit (Faculty of Sci-
ence, Cairo University). IR spectra were recorded using
KBr disks with a Mattson 5000 FTIR spectrometer, Faculty
of Science, Cairo University. The 1H NMR data were
measured in CDCl3 or DMSO-d6 on a Varian XL 200,
300 MHz instruments using TMS as an internal standard.
Chemical shifts were reported in ppm (d) downfield from
that of TMS and coupling constants are expressed in hertz.
Mass spectra were recorded on GC–MS QP-1000 EX.
Shimadzu Instrument (Faculty of Science, Cairo Univer-
sity). Reactions were monitored by thin layer chromatog-
raphy (TLC) using EM science silica gel coated plates with
visualization by irradiation with ultraviolet lamp. Elemental
analyses (C, H) were carried out at the Micro Analytical
Center of Cairo Univ., Giza, Egypt. The results were found
to be in good agreement ( 0.3%) with the calculated val-
ues. Microbiology screening was carried out in Botany
Department, Faculty of Science, Mansoura University,
under supervision Prof. Dr. Ellazeik, Y.A.O.
Ampicillin
21
14
26
15
14
14
14
14
26
13
14
1
2
3
4
6
7
18
19
21
26
(Yoshioka et al., 2003), the technique is simple, rapid to
perform, and capable of resolving mixtures of DNA frag-
ments that cannot be separated adequately by other sizing
procedures, such as density gradient centrifugation. Fur-
thermore, the location of DNA within the gel can be
determined directly: bands of DNA in the gel are stained
with low concentration of the fluorescent dye, ethidium
bromide. The method used to detect strand breakage is
based up on the different tail mobility of different forms of
bacterial DNA. Compounds 2 and 6 have strong degrada-
tive effect on DNA while the other compounds have slight
effect on DNA, these effect may be attributed to the
hydrolysis of glycosidic bond in DNA. The hydrolytic
effect of these compounds on the DNA may be useful in
the treatment and these compounds can be used as antitu-
mor agents after in vitro studies.
Reactions with Schiff bases: synthesis of 5-arylidene-2-
iminothiazolidin-4-ones 3 and 4
A mixture 2-iminothiazolidin-4-one (1) (0.5 g, 4.3 mmol)
and N-benzylideneaniline (0.78 g, 4.3 mmol) or N-(4-
methylbenzylidene)aniline (0.84 g, 4.3 mmol) in acetic acid
(10 cm3), refluxed for 8 h. The reaction mixture was left to
cool, poured onto ice. The formed precipitate was collected
by filtration, dried, and then purified by crystallization from
acetic acid to give the arylidenes 3 and 4, respectively.
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Med Chem Res (2012) 21:2615–2623
2621
(Z)-5-Benzylidene-2-iminothiazolidin-4-one (3)
ppm: 5.06 (s, 2H), 5.39 (s, 2H), 6.17 (s, 2H), 6.79–7.14 (m,
6H), 7.26–7.31 (m, 2H), 7.63 (s, 1H); MS (EI, 70 eV): m/z
(%): 365 (M?, 30), 260 (45), 178 (100), 140 (5). Anal.
calcd. for C19H15N3O3S (365.41):C, 62.45; H, 4.14%.
Found: C, 62.07; H, 3.79%.
Yellow crystals; yield 89%; mp 240–242°C (Lit (Ramsh
et al., 1983). 240–242°C); Rf = 0.60 [Pet. ether (40–60°C)/
ethyl acetate; (1:1)]; IR (KBr) t9max. cm-1: 3180, 3014, 1536,
1448, 1364, 690. Calcd. for C10H8N2OS (204.25).
(Z)-7-(4-Chlorobenzylidene)-3-phenyl-3,4-dihydro-2H-
(Z)-2-Imino-5-(4-methylbenzylidene)thiazolidin-4-one (4)
thiazolo[3,2-a][1,3,5]triazin-6(7H)-one (7)
Yellow crystals; yield 82%; mp 282–284oC (Lit (Ramsh
et al., 1983). 280-282oC); Rf = 0.57 [Pet. ether (40–60°C)/
ethyl acetate; (1:1)]. Calcd. for C11H10N2OS (218.27).
Yellow crystals; yield 40% (Method I), 95% (Method II);
mp 182–184°C; Rf = 0.38 [Pet. ether (40-60oC)/ethyl
acetate; (1:2)]; IR (KBr) t9max. cm-1: 2890, 3016, 1671,
1641, 1608, 1490, 1351, 1276, 696; 1H NMR (DMSO-d6) d
ppm: 5.07 (s, 2H), 5.41 (s, 2H), 6.97–7.34 (m, 5H), 7.70 (s,
4H), 7.76 (s, 1H); MS (EI, 70 eV): m/z (%): 355 (M?, 50),
357 (25), 328 (5), 252 (15), 169 (100). Anal. calcd. for
C18H14ClN3OS (355.84):C, 60.76; H, 3.97%. Found: C,
60.37; H, 3.66%.
(Z)-7-Arylidene-3-phenyl-3,4-dihydro-2H-thiazolo[3,2-
a][1,3,5]triazin-6(7H)-ones 5-7
General procedure
Method A A mixture of 3,4-dihydro-3-phenyl-2H-thiazol-
o[3,2-a][1,3,5]triazin-6(7H)-one (2) (0.47 g, 2 mmol) and
aromatic aldehydes namely; benzaldehyde (0.21 g,
2 mmol), benzo[d][1,3]dioxole-5-carbaldehyde (0.30 g,
2 mmol), or 4-chlorobenzaldehyde (0.28 g, 2 mmol) in
methanol (10 cm3) containing three drops of piperidine
was refluxed on steam bath for 6 h, the reaction mixture
left to cool. The precipitate formed was collected by fil-
tration, and then purified by crystallization from DMF to
afford compounds 5–7, respectively.
(E)-7-(4-((Z)-(6-Oxo-3-phenyl-3,4-dihydro-2H-
thiazolo[3,2-a][1,3,5]triazin-7(6H)-
ylidene)methyl)benzylidene)-3-phenyl-3,4-dihydro-2H-
isothiazolo[2,3-a][1,3,5] triazin-8(7H)-one (18)
A mixture of 2 (0.47 g, 2 mmol) and 2,20-(1,4-phenylene-
bis(methan-1-yl-1-ylidene))
dimalononitrile
(0.23 g,
1 mmol) or [terephthalaldehyde (0.13 g, 1 mmol) and
malononitrile (0.13 g, 2 mmol)] in methanol (10 cm3)
catalyzed by triethylamine (0.5 cm3) was refluxed on a
steam bath for 2 h. The precipitate formed while boiling
was collected by filtration, dried, and purified by crystal-
lization from DMSO to afford 18, yellow crystals; yield
83%; mp [360oC; Rf = 0.41 [Pet. ether (40–60°C)/ethyl
acetate; (1:3)]; IR (KBr) t9max. cm-1: 3026, 1670, 1610,
1498, 1380, 1278, 816, 756; MS (EI, 70 eV): m/z (%): 564
(M?, 3), 538 (5), 463 (5), 391 (15), 307 (20), 245 (3), 165
(4), 162 (60), 153 (5), 77 (100), 76 (23). Anal. calcd. for
C30H24N6O2S2 (564.68): C, 63.81; H, 4.28%. Found: C,
63.48; H, 3.93%.
Method B A mixture of 2 (0.47 g, 2 mmol) and ethyl
2-cyano-3-phenylacrylate (0.40 g, 2 mmol), ethyl 3-(benzo
[d][1,3]dioxol-5-yl)-2-cyanoacrylate (0.49 g, 2 mmol), or
ethyl 3-(4-chlorophenyl)-2-cyanoacrylate (0.47 g, 2 mmol),
in methanol (10 cm3) catalyzed by triethylamine (0.5 cm3).
Thereactionmixturewasrefluxedona steambathfor 1 h.The
precipitate formed while boiling was collected by filtration,
dried, and purified by crystallization from DMF to afford
compounds 5–7, respectively.
(Z)-7-Benzylidene-3-phenyl-3,4-dihydro-2H-
thiazolo[3,2-a][1,3,5]triazin-6(7H)-one (5)
(Z)-7-((Dimethylamino)methylene)-3-phenyl-3,4-
dihydro-2H-thiazolo[3,2-a][1,3,5]triazin-
6(7H)-one (19)
Yellow crystals; yield 27% (Method I); 95% (Method II);
mp 180–182°C (Lit (Ramsh et al., 1982). 180–181oC);
Rf = 0.33 [Pet. ether (40–60°C)/ethyl acetate (1:2)].
A mixture of 2 (0.94 g, 4 mmol) and DMF–DMA (0.48 g,
4 mmol) stirred in DMF (10 cm3) for 6 h. The reaction
mixture kept overnight at room temperature, then triturated
with ethanol (5 cm3). The precipitate formed was collected
by filtration, dried, and purified by column chromatography
using [pet. ether (60–80°C)/ethyl acetate (2:1)] to afford
19, yellow crystals; yield 56%; mp 170–172°C; Rf = 0.54
(Z)-7-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-phenyl-
3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazin-
6(7H)-one (6)
Yellow crystals; yield 35% (Method I), 95% (Method II);
mp 176–178oC; Rf = 0.36 [Pet. ether (40–60°C)/ethyl
acetate; (1:2)]; IR (KBr) t9max. cm-1: 2892, 1693, 1631,
1604, 1496, 1448, 1363, 1263; 1H NMR (DMSO-d6) d
[Pet. ether (40–60°C)/ethyl acetate; (2:1)]; IR (KBr) t9max
.
cm-1: 3002, 2910, 3860, 1378, 1620, 1494, 1430, 1350,
123

2622
Med Chem Res (2012) 21:2615–2623
1
1310, 1180, 1094, 768; H NMR (DMSO-d6) d ppm: 3.04
(s, 6H), 4.92 (s, 2H), 5.23 (s, 2H), 6.92–7.06 (m, 3H),
7.25–7.30 (m, 2H), 7.46 (s, 1H); MS (EI, 70 eV): m/z (%):
288 (M?, 25), 183 (68), 129 (55), 101 (100). Anal. calcd.
for C14H16N4OS (288.37): C, 58.31; H, 5.59%. Found: C,
57.94; H, 5.26%.
1255, 1126, 810, 760; MS (EI, 70 eV): m/z (%): 580 (M?-
OH, 1), 182 (36), 117 (95), 105 (100), 77 (17). Anal. calcd.
for C28H24N10O2S2 (596.69): C, 56.36; H, 4.05%. Found:
C, 56.03; H, 3.72%.
(E)-4-Oxo-N3,N5-diphenyl-2-
(phenylcarbamothioylimino)thiazolidine-3,5-
bis(carbothioamide) (25)
(E)-7-{2-[4-(Phenyl) or (chlorophenyl)]hydrazono}-3-
phenyl-3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazin-
6(7H)-ones 20, 21, and (7E,7’Z)-7,7’-(2,2’-(1,4-
phenylene)bis(hydrazin-2-yl-1-ylidene))bis(3-phenyl-
3,4-dihydro-2H-thiazolo[3,2-a][1,3,5]triazin-6(7H)-
one) (22)
A
mixture of 2-iminothiazolidin-4-one (1) (0.5 g,
4.3 mmol) and phenyl isothiocyanate (1.67 g, 12.4 mmol)
in methanol (10 cm3) and methoxide (10 mmol) was stir-
red for 8 h. the reaction mixture then basified by ammonia
and the formed precipitate was collected by filtration,
dried, and then purified by crystallization from methanol to
furnish 25, Red crystals; yield 65%; mp 180–182°C;
Rf = 0.49 [Pet. ether (40–60°C)/ethyl acetate; (2:1)]; IR
(KBr) t9max. cm-1: 3225, 3180, 3014, 1536, 1448, 1364,
690; MS (EI, 70 eV): m/z (%): 521 (M?, 4), 368 (28), 83
(100). Anal. calcd. for C24H19N5OS4 (521.7): C, 55.25; H,
3.67%. Found: C, 55.63; H, 3.34%.
To a solution of 2 (0.47 g, 2 mmol), and the diazonium salt
of aromatic amines namely; benzenediazonium chloride
(0.28 g, 2 mmol), 4-methylbenzenediazonium chloride
(0.31 g, 2 mmol), or benzene-1,4-bis(diazonium) chloride
(0.41 g, 2 mmol) in pyridine (10 cm3), was stirred in an ice
path, then left for overnight in the refrigerator then poured
onto ice water. The precipitate formed was collected by
filtration, dried, and then purified by crystallization using
DMF to give 20, 21, and 22, respectively.
Methyl 6-oxo-2,4-dithioxo-2,4,6,7-tetrahydro-
thiazolo[3,2-c][1,3,5]thiadiazine-7-carbodithioate (26)
(E)-3-Phenyl-7-(2-phenylhydrazono)-3,4-dihydro-2H-
thiazolo[3,2-a][1,3,5]triazin-6(7H)-one (20)
A
mixture of 2-iminothiazolidin-4-one (1) (0.5 g,
4.3 mmol), in DMSO (10 cm3) and NaOH (0.33 g,
8.6 mmol), carbon disulfide (0.94 g, 12.4 mmol) was
added. The reaction mixture was stirred for 8 h, then
dimethyl sulfate (1.6 g, 12.4 mmol) was added and
continuing stirring for further 6 h, then poured into ice and
acidified using acetic acid. The formed precipitate was
collected by filtration, dried, and then purified by crystal-
lization from DMSO to give 26, red crystals; yield 58%; mp
[360°C; Rf = 0.65 [Pet. ether (40–60°C)/ethyl acetate;
(1:1)]; IR (KBr) t9max. cm-1: 2994, 1662, 1526, 1014, 830;
MS (EI, 70 eV): m/z (%): 309 (M?-CH3, 8), 262 (100), 261
(12), 149 (84). Anal. calcd. for C7H4N2OS6 (324.51): C,
25.91; H, 1.24%. Found: C, 25.62; H, 1.54%.
Yellow crystals; yield 60%; mp 210–212°C; Rf = 0.60
[Pet. ether (40–60°C)/ethyl acetate; (1:1)]; MS (EI, 70 eV):
m/z (%): 337 (M?, 20), 232 (76), 150 (100), 77 (73). Anal.
calcd. for C17H15N5OS (337.4): C, 60.52; H, 4.48%.
Found: C, 60.14; H, 4.14%.
(E)-3-Phenyl-7-(2-p-tolylhydrazono)-3,4-dihydro-2H-
thiazolo[3,2-a][1,3,5]triazin-6(7H)-one (21)
Yellow crystals; yield 87%; mp 225–222°C; Rf = 0.58
[Pet. ether (40–60°C)/ethyl acetate; (2:1)]; IR (KBr) t9max
.
cm-1: 3225, 3186, 3028, 2921, 1681, 1625, 1554, 1508,
1
1335, 1262, 1123, 813, 762; H NMR (DMSO-d6) d ppm:
2.23 (s, 3H), 5.04 (s, 2H), 5.33 (s, 2H), 6.94–7.10 (m, 7H),
7.27–7.31 (m, 2H), 10.21 (s, 1H); MS (EI, 70 eV): m/z (%):
352 (M??1, 5), 351 (M?, 15), 129 (55), 246 (60), 164
(100), 104 (90). Anal. calcd. for C18H17N5OS (351.43): C,
61.52; H, 4.88%. Found: C, 61.16; H, 4.56%.
Antibacterial activity
The tested compounds were evaluated by the agar diffusion
technique (Cruickshank et al., 1975), in this method
Escherichia coli (Gram -ve) were used as test organism.
Agar nutrient medium was prepared, autoclaved, and
poured into sterilized petri-dishes. Few drops of dense
bacterial suspension were gently spread over the medium
surface using a sterilized spatula. The bacterial smear was
left to dry and then a number of pores were made on agar-
nutrient medium using a sterilized crock porer. For
screening the antibacterial activities, solution of the tested
(7E,70Z)-7,70-(2,20-(1,4-Phenylene)bis(hydrazin-2-yl-1-
ylidene))bis(3-phenyl-3,4-dihydro-2H-thiazolo[3,2-
a][1,3,5]triazin-6(7H)-one) (22)
Brown crystals; yield 76%; mp [360°C; Rf = 0.63 [Pet.
ether (40–60°C)/ethyl acetate; (1:3)]; IR (KBr) t9max. cm-1
3230, 3193, 3016, 2910, 1675, 1620, 1545, 1500, 1325,
:
123

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2623
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