Facile novel synthesis and reactions of thiazolidin-4-one derivatives for antimicrobial agents

Article abstract of DOI:10.1080/00397910903318674

A facile and fast procedure for synthesis of 3-phenyl-cyclohexane(1'-2) thiazolidin-4-one (1), which underwent condensation with glucose and p-chlorobenzaldehyde to afford 2 and 3, respectively. Compound 3 was used as precursor for the preparation of some

Full text of DOI:10.1080/00397910903318674

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Facile Novel Synthesis and Reactions
of Thiazolidin-4-one Derivatives for
Antimicrobial Agents
Hayam H. Sayed a , Eman M. H. Morsy a & Eman R. Kotb a
a Photochemistry Department, National Research Centre, Dokki,
Cairo, Egypt
Version of record first published: 09 Aug 2010.
To cite this article: Hayam H. Sayed , Eman M. H. Morsy & Eman R. Kotb (2010): Facile Novel
Synthesis and Reactions of Thiazolidin-4-one Derivatives for Antimicrobial Agents, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:18, 2712-2722
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Synthetic Communications1, 40: 2712–2722, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903318674
FACILE NOVEL SYNTHESIS AND REACTIONS OF
THIAZOLIDIN-4-ONE DERIVATIVES FOR
ANTIMICROBIAL AGENTS
Hayam H. Sayed, Eman M. H. Morsy, and Eman R. Kotb
Photochemistry Department, National Research Centre, Dokki, Cairo, Egypt
A facile and fast procedure for synthesis of 3-phenyl-cyclohexane(10-2)thiazolidin-4-one
(1), which underwent condensation with glucose and p-chlorobenzaldehyde to afford 2
and 3, respectively. Compound 3 was used as precursor for the preparation of some fused
heterocyclic compounds 4–7. Compound 4 was alkylated using dichloroacetone and chlor-
oacetic acid to afford 8 and 9, respectively. Also, it reacted with acrylonitrile and hydrazine
hydrate to afford 10 and 11, respectively. Compound 9 was condensed with p-chlorobenzal-
dehyde and glucose to afford 12 and 13, respectively. Selected members of the synthesized
compounds were screened for antimicrobial activity.
Keywords: Antimicrobial activities; bis-thiazolopyrimidine; pyrazolothiazole; thiazolopyridine;
thiazolopyrimidine
INTRODUCTION
Thiazolidin-4-one derivatives exhibit high activity in vitro against mycobacter-
ium tuberculosis (TB) and as drugs to treat HIV and cancer.[1–3] Recently, 2-aryl-4-
thiazolidinone has been synthesized and found to exhibit potent selective antiplatelet
activating factors both in vitro and in vivo and anti-inflammatory,[4] antibacterial,
anticancer,[5] and anti-HIV-1 activities.[6] Spiroheterocyclic compounds including
thiazolidine moiety have antimicrobial activity.[7] Both pyrazolothiazole and thiazo-
lopyrimidine moieties have potent kinase modulators[8] and are used in pharmaceu-
tical compositions.[9] The latter compound has analgesic and anti-Parkinson
activities[10] and inhibits the growth of parasite Trypanosoma cruzi.[11] In continu-
ation of our search of new compounds with anticipated biological activity starting
from accessible material,[12–19] we aimed to obtain new compounds of the fused thia-
zole system, which are expected to possess notable chemical and biological activities.
RESULTS AND DISCUSSION
We have synthesized 3-phenyl-cyclohexane(10-2)thiazolidin-4-one (1) in good
yield via a one-pot reaction to afford white crystals (cf. the Experimental section;
Received June 16, 2009.
Address correspondence to Hayam H. Sayed, Photochemistry Department, National Research
Centre, Dokki, Cairo, Egypt. E-mail: Hayamsayed@yahoo.com
2712

SYNTHESIS OF THIAZOLIDIN-4-ONE DERIVATIVES
2713
Scheme 1. Condensation and Michael reaction of thiazlidine with different reagents.
Scheme 1). The assigned structure was proved based on elemental and spectral analy-
sis. The infrared (IR) spectrum of the isolated product showed absorption bands at
1713 cmꢀ1 corresponding to the (CO) group. The 1H NMR spectrum revealed
signals at d 1.3 ppm and d 1.8 ppm attributed to cyclohexane protons, signals at d
3.40 ppm attributed to thiazole ring protons, and a multiplet at d 7.0–7.3 ppm
corresponding to aromatic protons. Furthermore, the mass spectra gave a molecular

2714
H. H. SAYED, E. M. H. MORSY, AND E. R. KOTB
ion peak at m=z 247.1. Also, compound 1 was confirmed chemically via
condensation with D-glucose and p-chlorobenzaldehyde to afford 2 and 3, respect-
ively. The structures of the latter compounds were elucidated from their correct data
(cf. the Experimental section). For example, the IR spectrum of compound 3 showed
1
an absorption band at 1687 cmꢀ1 (CO) due to conjugation, H NMR spectrum
showed absence of thiazolomethylene protons, and its mass spectrum showed the
Mþ peak at 369.3, all of which support its molecular formula. Compound 3 was used
as starting material for further syntheses of other heterocyclic compounds. It reacted
with thiourea, hydrazine hydrate derivatives, malononitrile, and ethyl cyanoacetate
to afford compounds 4–7, respectively (Scheme 1). The structures of these
compounds were confirmed from their correct data (cf. the Experimental section).
Scheme 2. Alkylation and disulfurization of thiazolopyrimidine.

SYNTHESIS OF THIAZOLIDIN-4-ONE DERIVATIVES
2715
Scheme 3. Condensation of bis-thiazolopyrimidine with aldehyde and glucose.
For example, the IR spectrum of compound 4 showed the absence of the band
characteristic for (CO) and the presence of absorption bands at 3120, 3170 cmꢀ1
(NH), and 1213 cmꢀ1(CS). Also, its 1H NMR spectrum revealed signals at d
4.60 ppm characteristic of the pyrimidine ring and at d 8.90 and 11.20 ppm for
2NH protons that are D2O exchangeable. Mass spectra showed Mþ at 427.3, which
supports its molecular formula (cf. the Experimental section; Scheme 1).
On the other hand, compound 4 was allowed to react with halo compounds,
namely dichloroacetone and=or chloroacetic acid, to afford compounds 8 and 9,
respectively. Also, compound 4 was reacted with acrylonitrile via Michael addition
to afford 10, and its reaction with hydrazine hydrate afforded hydrazino pyrimidine
derivative 11 (Scheme 2).
Finally, bis-thiazolopyrimidine derivative
9
was condensed with p-
chlorobenzaldehyde and D-glucose to afford 12 and 13, respectively. The structures
of all compounds were confirmed by their correct data (cf. the Experimental section;
Scheme 3).
Antimicrobial Activity
Some of the synthesized compounds 4, 6, 7, 10, and 15 were tested in
concentrations of 0.1 g=ml using dimethylformamide (DMF) as a solvent. The micro-
organisms used were as follows: Gram-negative bacteria, E. coli and P. aeruginosa;
Gram-positive bacteria, B. subtilis, S. aureus, and S. lutea; and yeast, C. albicans.

2716
H. H. SAYED, E. M. H. MORSY, AND E. R. KOTB
Medium
The cap-assay method containing (g=l) peptone (6.0), yeast extract (3.0), meat
extract (1.5), glucose (1.0), and agar (20.0) were used. The medium was sterilized and
divided while hot (50–60 ꢁC) into 15-ml portions among sterile Petri dishes 9 cm in
diameter. One ml of the spore suspension of each microorganism was spread all over
the surface of the cold solid medium placed in the Petri dish.
Method[20]
Portions of 0.5 g of each tested compound were dissolved in 5 ml of DMF. An
amount of 0.1 ml of the test solution was placed on Whatman paper disc, 9 mm in
diameter, and the solvent was left to evaporate. These saturated discs were placed
carefully on the surface of the inoculated solid medium; each Petri dish contained
at least three discs. The Petri dishes were incubated at 5 ꢁC for an hour to permit
good diffusion, then transferred to an incubator at 85 ꢁC overnight, and then
examined. The results were recorded by measuring the inhibition zone diameters.
CONCLUSION
The results of antimicrobial activity of compounds 1, 4, 5a, 6, and 13 showed
interesting degrees of antibacterial activity. Penicillin was used as a reference to
evaluate the potency of the tested compounds. Compounds 1, 4, 5a, 6, and 13 showed
greater antibacterial activities than the standard drug (penicillin). Compound 7 did
not show any activity against the tested microorganisms, whereas compounds 6 and
11 showed greater activity against C. albicans than the standard drug (nystatin).
These results of biological activities encourage further work on such ring system
(Table 1).
Table 1. Antimicrobial activities of the tested compounds
Inhibition zone (mm)
Gram-negative bacteria
Gram-positive bacteria
Tested compounds
and standards
Yeast
C. albicans
E. coli.
P. aeruginosa
B. subtilis
S. aureus
S. lutea
Pencillin
Nystalin
15
—
16
17
18
15
—
—
17
13
—
20
20
15
20
—
—
22
20
—
20
18
15
20
—
—
22
15
—
—
10
12
10
—
—
—
17
—
25
25
20
—
—
—
24
—
15
—
—
—
20
—
25
—
1
4
5a
6
7
11
13
Notes. Highly sensitive: inhibition zone 21–30 mm.
Fairly sensitive: inhibition zone 16–20 mm.
Slightly sensitive: inhibition zone 10–15 mm.

SYNTHESIS OF THIAZOLIDIN-4-ONE DERIVATIVES
2717
EXPERIMENTAL
All melting points are uncorrected and measured using an Electro-thermal IA
9100 apparatus (Shimadzu, Japan). Infrared (IR) spectra were recorded as potassium
bromide pellets on a Perkin-Elmer 1650 spectrophotometer (Shimadzu) at the
1
National Research Centre, Cairo, Egypt. H NMR spectra were determined on a
Jeol-Ex-300 NMR spectrometer, and chemical shifts were expressed as part per mil-
lion (ppm; d values) against tetramethylsilane (TMS) as internal reference. Mass
spectra (MS) were recorded on EI þQ1 MSLMR UPLR, at the National Research
Centre, Cairo, Egypt. Microanalyses were operated using a Mario El Mentar appar-
atus at the Organic Microanalysis Unit, National Research Centre, Cairo, Egypt,
and the results were within the accepted range (ꢂ0.20) of the calculated values.
3-Phenyl-cyclohexane(1’-2)thiazolidin-4-one (1)
A mixture of aniline (1.86 mL, 20 mmol), cyclohexanone (1.96 mL, 20 mmol),
and 2-mercaptoacetic acid (1.96 mL, 20 mmol) in 50 mL dry benzene was refluxed
for 8 h. The solvent was evaporated under reduced pressure. The formed solid was
filtered off, dried, and recrystallized from ethanol to afford compound 1 in 56%
1
yield; mp 166–167 ꢁC. IR spectrum (KBr, n, cmꢀ1): 1713 (CO); H NMR spectrum
(CDCl3, d ppm):1.30 (t, J ¼ 3.50 Hz, 6H, 3CH2), 1.80 (t, J ¼ 2.40 Hz, 4H, 2CH2), 3.40
(s, 2H, thiazole H), 7.00–7.30 (m, 5H, Ar-H); MS, m=z (%): 247.1 (Mþ, 35). Analysis
for C14H17NOS (247.36) required: C, 67.98; H, 6.93; N, 5.66; S, 12.96; found: C,
67.95; H, 6.90; N, 5.58; S, 13.00.
5-(2,3,4,5,6-Pentahydroxy-hexylidene)-3-phenyl-cyclohexane(1’-2)
thiazolidin-4-one (2)
Compound 1 (1.23 gm, 5 mmol) in absolute ethanol (30 mL) and few drops of
acetic acid were added to a solution of D-glucose (0.83 g, 5 mmol) in water (0.5 mL)
with stirring at 60 ꢁC for 5 h. The product that separated out of cooling was filtered
off, washed with water followed by ethanol, and dried to afford compound 2 in 60%
yield; mp 149–150 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3410 (OH), 1700 (CO); 1H NMR
spectrum (CDCl3, d ppm):1.29 (t, J ¼ 3.45 Hz, 6H, 3CH2), 1.78 (t, J ¼ 2.43 Hz, 4H,
2CH2), 3.30–3.95 (m, 6H, glucose), 4.60–4.90 (m, 5H, OH, D2O exchangeable),
6.60 (d, J ¼ 1.68 Hz, 1H, methylene), 7.00–7.70 (m, 5H, Ar-H). Analysis for
C20H27NO6S (409.5) required: C, 58.66; H, 6.65; N, 3.42; S, 7.83; found: C, 58.72;
H, 6.70; N, 3.46; S, 7.90.
5-(4-Chloro-benzylidene)-3-phenyl-cyclohexane(1’-2)
thiazolidin-4-one (3)
A mixture of compound 1 (1.23 g, 5 mmol) and 4-chlorobenzaldehyde (0.7 ml,
5 mmol) was refluxed in a mixture of glacial acetic acid and acetic anhydride (3:1)
containing anhydrous sodium acetate (0.36 g, 5 mmol) for 3 h. The reaction mixture
was cooled and poured gradually with stirring into cool water (100 mL). The formed
solid was filtered off, dried, and recrystallized from methanol to give compound 3 in

2718
H. H. SAYED, E. M. H. MORSY, AND E. R. KOTB
1
65% yield; mp 189–190 ꢁC. IR spectrum (KBr, n, cmꢀ1): 1687 (CO); H NMR spec-
trum (CDCl3, d ppm):1.28 (t, J ¼ 3.30 Hz, 6H, 3CH2), 1.76 (t, J ¼ 2.36 Hz, 4H,
2CH2), 7.20–7.70 (m, 10H, Ar-H þmethylene H); MS, m=z (%): 369.3 (Mþ, 17).
Analysis for C21H20ClNOS (369.91) required: C, 68.19; H, 5.45; Cl, 9.58; N, 3.79;
S, 8.67; found: C, 68.25; H, 5.42; Cl, 9.64; N, 4.00; S, 8.72.
7-(4-Chloro-phenyl)-3-phenyl-2,3,6,7-tetrahydro-cyclohexane(1’-2)
thiazolo[4,5-d]pyrimidine-5-thione (4)
A mixture of compound 3 (1.88 g, 5 mmol) and thiourea (0.76 g, 10 mmol) was
refluxed in ethanolic sodium hydroxide (1 g, 30 ml) for 4 h. The reaction mixture was
cooled and poured into water (100 ml). The formed solid was filtered off, dried, and
recrystallized from dioxane to give compound 4 in 56% yield; mp 273–274 ꢁC. IR
spectrum (KBr, n, cmꢀ1): 3170, 3120 (2NH), 1213 (CS); 1H NMR spectrum
(DMSO-d6, d ppm):1.28 (t, J ¼ 3.18 Hz, 6H, 3CH2), 1.72 (t, J ¼ 2.20 Hz, 4H,
2CH2), 4.60 (s, 1H, pyrimidine H), 6.50–7.20 (m, 9H, Ar-H), 8.90 (s, 1H, NH,
D2O exchangeable), 11.20 (s, 1H, NH, D2O exchangeable); MS, m=z (%): 427.3
(Mþ, 19). Analysis for C22H22ClN3S2 (428.02) required: C, 61.74; H, 5.18; Cl,
8.28; N, 9.82; S, 14.98; found: C, 61.52; H, 5.20; Cl, 8.30; N, 9.90; S, 14.76.
3-(4-Chloro-phenyl)-3-phenyl-2,3,6,7-tetrahydro-cyclohexane(1’-5)
pyrazolo[3,4-d]thiazole (5a)
A mixture of compound 3 (1.88 g, 5 mmol) and hydrazine hydrate (0.40 mL,
10 mmol) was refluxed in absolute ethanolic (30 ml) for 4 h. The solid substance
was filtered off, dried, and recrystallized from dioxane to give compound 5a in
1
80% yield; mp 209–210 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3100, 3118 (2NH); H
NMR spectrum (DMSO-d6, d ppm):1.30 (t, J ¼ 3.25 Hz, 6H, 3CH2), 1.80 (t,
J ¼ 2.32 Hz, 4H, 2CH2), 4.70 (s, 1H, pyrazole H), 6.60–7.30 (m, 9H, Ar-H), 9.20
(s, 1H, NH, D2O exchangeable), 10.50 (s, 1H, NH, D2O exchangeable); MS, m=z
(%): 383.2 (Mþ, 28). Analysis for C21H22ClN3S (383.94) required: C, 65.69; H,
5.78; N, 10.94; S, 8.35; found: C, 66.30; H, 5.81; N, 11.00; S, 8.55.
3-(4-Chloro-phenyl)-2,3-diphenyl-2,6,7-trihydro-cyclohexane(1’-5)
pyrazolo[3,4-d]thiazole (5b)
A mixture of compound 3 (1.88 g, 5 mmol) and phenyl hydrazine (1.06 mL,
10 mmol) was refluxed in absolute ethanolic (50 ml) for 4 h. The reaction mixture
was cooled, and the solid substance was filtered off, dried, and recrystallized from
dioxane to give compound 5b in 80% yield; mp 263–264 ꢁC. IR spectrum (KBr, n,
1
cmꢀ1): 3150 (NH); H NMR spectrum (DMSO-d6, d ppm): 1.29 (t, J ¼ 3.20 Hz,
6H, 3CH2), 1.75 (t, J ¼ 2.24 Hz, 4H, 2CH2), 4.58 (s, 1H, pyrazole H), 6.50–7.20
(m, 14H, Ar-H), 9.40 (s, 1H, NH, D2O exchangeable; MS, m=z (%): 459.4 (Mþ,
35). Analysis for C27H26ClN3S (460.03) required: C, 70.49; H, 5.70; N, 9.13; S,
6.97; found: C, 70.53; H, 5.62; N, 9.10; S, 7.00.

SYNTHESIS OF THIAZOLIDIN-4-ONE DERIVATIVES
2719
5-Amino-7-(4-chloro-phenyl)-3-phenyl-2,3-dihydro-cyclohexane(1’-2)
thiazolo[4,5-b]pyridine-6-carbonitrile (6)
A mixture of compound 3 (1.88 g, 5 mmol), malononitrile (0.66 g, 10 mmol),
and ammonium acetate (1.53 g, 20 mmol) was refluxed in glacial acetic acid (40 ml)
for 30 h. The reaction mixture was cooled and poured into water. The formed solid
was filtered off, dried, and recrystallized from methanol to give compound 6 in 50%
yield; mp 222–223 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3417–3220 (NH2), 2216 (CN); 1H
NMR spectrum (DMSO-d6, d ppm): 1.28 (t, J ¼ 3.24 Hz, 6H, 3CH2), 1.72 (t,
J ¼ 2.60 Hz, 4H, 2CH2), 6.50–7.50 (m, 9H, Ar-H), 7.80 (s, 2H, NH2, D2O exchange-
able); MS, m=z (%): 432.3 (Mþ, 90). Analysis for C24H21ClN4S (432.94) required: C,
66.58; H, 4.89; N, 12.94; S, 7.41; found: C, 66.60; H, 4.93; N, 13.00; S, 7.46.
7-(4-Chloro-phenyl)-5-oxo-3-phenyl-2,3,4,5-tetrahydro-
cyclohexane(1’-2)thiazolo[4,5-b]pyridine-6-carbonitrile (7)
A mixture of compound 3 (1.88 g, 5 mmol), ethyl cyanoacetate (1.13 g,
10 mmol), and anhydrous ammonium acetate (1.60 g, 20 mmol) was refluxed in gla-
cial acetic acid (40 ml) for 20 h. The reaction mixture was cooled and poured into
water. The formed solid was filtered off, dried, and recrystallized from acetic acid
to give compound 7 in 55% yield; mp 251–252 ꢁC. IR spectrum (KBr, n, cmꢀ1):
1
3150 (NH), 2222 (CN), 1687 (CO); H NMR spectrum (DMSO-d6, d ppm): 1.29
(t, J ¼ 3.33 Hz, 6H, 3CH2), 1.76 (t, J ¼ 2.23 Hz, 4H, 2CH2), 6.60–7.30 (m, 9H,
Ar-H), 10.20 (s, 1H, NH, D2O exchangeable); MS, m=z (%): 433.5 (Mþ, 83). Analysis
for C24H20ClN3OS (433.95) required: C, 66.43; H, 4.65; N, 9.68; S, 7.39; found: C,
66.50; H, 4.66; N, 9.73; S, 7.42.
1-Chloro-3-[6-(3-chloro-2-oxo-propyl)-7-(4-chloro-phenyl)-
3-phenyl-5-thioxo-3,5,6,7-tetrahydro-cyclohexane(1’-2)
thiazolo[4,5-d]pyrimidin-4-yl]-propan-2-one (8)
A mixture of compound 4 (1.67 g, 2.5 mmol) and dichloroacetone (0.73 g,
50 mmol) was refluxed in ethanolic sodium hydroxide (0.4 g, 30 ml) for 3 h. The reac-
tion mixture was cooled and poured into water. The formed solid was filtered off,
dried, and recrystallized from ethanol to give compound 8 in 70% yield; mp
1
182–183 ꢁC. IR spectrum (KBr, n, cmꢀ1): 1703, 1709 (CO), 1202 (CS); H NMR
spectrum (DMSO-d6, d ppm): 1.28 (t, J ¼ 3.24 Hz, 6H, 3 ꢃ CH2), 1.74 (t, J ¼ 2.32 Hz,
Hz, 4H, 2CH2), 4.52 (s, 4H, 2CH2), 4.58 (s, 1H, pyrimidine), 6.30 (s, 4H, 2CH2),
6.50–7.20 (m, 9H, Ar-H); MS, m=z (%): 607 (Mþ, Cl35, 33), 609 (Mþ, Cl37, 27).
Analysis for C28H28Cl3N3O2S2 (609.03) required: C, 55.22; H, 4.63; N, 6.90; S,
10.53; found: C, 55.00; H, 4.65; N, 7.00; S, 10.65.
9-(4-Chloro-phenyl)-3-phenyl-3,9-dihydro-cyclohexane(1’-2)
bisthiazolo[3,2-a;4’,5’-d]pyrimidin-7-one (9)
A mixture of compound 4 (1.67 g, 2.5 mmol) and chloroacetic acid (0.26 g,
2.5 mmol) was refluxed in a mixture of glacial acetic acid and acetic anhydride

2720
H. H. SAYED, E. M. H. MORSY, AND E. R. KOTB
(3:1) containing anhydrous sodium acetate (0.18 g, 2.5 mmol) for 3 h. The reaction
mixture was cooled and poured into water. The formed solid was filtered off, dried,
and recrystallized from methanol to give compound 9 in 75% yield; mp 182–183 ꢁC.
IR spectrum (KBr, n, cmꢀ1): 1703 (CO); 1H NMR spectrum (CDCl3, d ppm):1.29 (t,
J ¼ 3.28 Hz, 6H, 3CH2), 1.76 (t, J ¼ 2.32 Hz, 4H, 2CH2), 3.40 (s, 2H, thiazolone),
5.60 (s, 1H, pyrimidine), 6.50–7.30 (m, 9H, Ar-H); MS, m=z (%): 467.1 (Mþ, 30).
Analysis for C24H22ClN3OS2 (468.04) required: C, 61.59; H, 4.74; N, 8.98; S,
13.70; found: C, 61.38; H, 4.76; N, 9.00; S, 13.75.
3-[7-(4-Chloro-phenyl)-3-phenyl-2,3,6,7-tetrahydro-cyclohexane
(1’-2)thiazolo[4,5-d]pyrimidin-5-ylsulfanyl]-propionitrile (10)
A mixture of compound 4 (1.67 g, 2.5 mmol) and acrylonitrile (0.13 mL,
2.5 mmol) was refluxed in absolute ethanol (30 mL) for 3 h. The formed solid was fil-
tered off, dried, and recrystallized from ethanol to give compound 10 in 70% yield;
mp 172–173 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3186 (NH), 2217 (CN); 1H NMR spec-
trum (CDCl3, d ppm):1.28 (t, J ¼ 3.30 Hz, 6H, 3CH2), 1.74 (t, J ¼ 2.34 Hz, 4H,
2CH2), 2.70 (t, J ¼ 4.50 Hz, 2H, CH2), 3.0 (t, J ¼ 6.30 Hz, 2H, CH2), 4.60 (s, 1H,
pyrimidine), 6.60–7.30 (m, 9H, Ar-H), 9.6 (s, 1H, NH, D2O exchangeable); MS,
m=z (%): 480.2 (Mþ, 23). Analysis for C25H25ClN4S2 (481.08) required: C, 62.42;
H, 5.24; N, 11.65; S, 13.33; found: C, 62.50; H, 5.28; N, 11.60; S, 13.13.
[7-(4-Chloro-phenyl)-3-phenyl-2,3,6,7-tetrahydro-cyclohexane
(1’-2)thiazolo[4,5-d]pyrimidin-5-yl]-hydrazine (11)
A mixture of compound 4 (1.67 g, 2.5 mmol) and hydrazine hydrate 99%
(20 mL) was refluxed for 8 h. The reaction mixture was cooled and poured into
water. The formed solid was filtered off, dried, and recrystallized from methanol
to give compound 11 in 65% yield; mp 167–168 ꢁC. IR spectrum (KBr, n, cmꢀ1):
1
3310–3313 (NH2), 3156, 3170 (NH); H NMR spectrum (CDCl3, d ppm): 1.28 (t,
J ¼ 3.24 Hz, 6H, 3CH2), 1.76 (t, J ¼ 2.34 Hz, 4H, 2CH2), 4.2 (s, 2H, NH2, D2O
exchangeable), 4.70 (s, 1H, pyrimidine), 5.6 (s, 1H, NH, D2O exchangeable),
6.40–7.20 (m, 9H, Ar-H), 9.6 (s, 1H, NH, D2O exchangeable); MS, m=z (%):
425.24 (Mþ, 24). Analysis for C22H24ClN5S (425.98) required: C, 62.03; H, 5.68;
N, 16.44; S, 7.53; found: C, 62.25; H, 5.70; N, 16.25; S, 7.45.
6-(4-Chloro-benzylidene)-9-(4-chloro-phenyl)-3-phenyl-3,9-dihydro-
cyclohexane(1’-2)bisthiazolo[3,2-a;4’,5’-d]pyrimidin-7-one (12)
A mixture of compound 9 (1.17 g, 2.5 mmol) and 4-chlorobenzaldehyde (0.35 g,
2.5 mmol) was refluxed in a mixture of glacial acetic acid=acetic anhydride (3:1)
containing anhydrous sodium acetate (0.18 g, 2.5 mmol) for 3 h. The reaction mix-
ture was cooled and poured gradually with stirring into cool water (100 mL). The
formed solid was filtered off, dried, and recrystallized from dioxane to give 12 in
1
70% yield; mp 206–207 ꢁC. IR spectrum (KBr, n, cmꢀ1): 1693 (CO); H NMR spec-
trum (DMSO-d6, d ppm): 1.29 (t, J ¼ 3.28 Hz, 6H, 3CH2), 1.78 (t, J ¼ 2.34 Hz, 4H,
2CH2), 5.6 (s, 1H, pyrimidine), 6.50–7.30 (m, 14H, Ar-Hþmethylene H); MS, m=z

SYNTHESIS OF THIAZOLIDIN-4-ONE DERIVATIVES
2721
(%): 589.1 (Mþ, Cl35, 29), 591 (Mþ, Cl37, 25). Analysis for C31H25Cl2N3OS2
(590.59) required: C, 63.04; H, 4.27; N, 7.11; S, 10.86; found: C, 62.98; H, 4.22;
N, 7.00; S, 10.76.
9-(4-Chloro-phenyl)-6-(2,3,4,5,6-pentahydroxy-hexylidene)-3-phenyl-
3,9-dihydro-cyclohexane(1’-2)bisthiazolo[3,2-a;4’,5’-d]pyrimidin-
7-one (13)
Compound 9 (1.17 g, 2.5 mmol) in dioxane (25 mL) containing a few drops of
acetic acid was stirring into a solution of glucose (0.83 g, 2.5 mmol) in water (0.5 ml)
at 60 ꢁC for 4 h. The product that separated out on cooling was filtered off, washed
with water followed by ethanol, and then dried to give compound 13 in 55% yield;
mp 170–171 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3380–3400 (OH), 1705 (CO); 1H
NMR spectrum (CDCl3, d ppm): 1.28 (t, J ¼ 3.40 Hz, 6H, 3CH2), 1.76 (t,
J ¼ 2.40 Hz, 4H, 2CH2), 3.32–3.98 (m, 6H, CH of glucose), 4.7 (m, 5H, OH, D2O
exchangeable), 5.5 (d, J ¼ 1.66 Hz, 1H, methylene H), 5.6 (s, 1H, pyrimidine),
6.50–7.20 (m, 9H, Ar–H). Analysis for C30H32ClN3O6S2 (630.18) required: C,
57.18; H, 5.12; N, 6.67; S, 10.18; found: C, 57.00; H, 5.15; N, 6.72; S, 10.23.
ACKNOWLEDGMENT
We are thankful to Dr. Naiera A. M. Abdel Wahed, Natural and Microbial
Products Department, National Research Centre, for biological evaluation.
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