A novel synthesis of some new pyrimidine and thiazolopyrimidine derivatives for anticancer evaluation

Article abstract of DOI:10.1080/10426500701313912

Diaryl-oxiran-2-yl methanones (2) were prepared and reacted with thiourea to give 2-thioxo-tetrahydro-pyrimidine-5(2H)-ones (3).The latter compounds reacted with bromoacetic acid to afford the title compounds (4). Also some new derivatives were prepared f

Full text of DOI:10.1080/10426500701313912

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A Novel Synthesis of
Some New Pyrimidine and
Thiazolopyrimidine Derivatives
for Anticancer Evaluation
E. E. Flefel a , M. A. Salama a , M. El-Shahat a , M. A.
El-Hashash b & A. F. El-Farargy c
a Photochemistry Department, National Research
Centre, Dokki, Cairo, Egypt
b Chemistry Department, Faculty of Science, Ain
Shams University, Abassia, Cairo, Egypt
c Chemistry Department, Faculty of Science, Zagazig
University, Egypt
Version of record first published: 15 Jun 2007.
To cite this article: E. E. Flefel , M. A. Salama , M. El-Shahat , M. A. El-Hashash
& A. F. El-Farargy (2007): A Novel Synthesis of Some New Pyrimidine and
Thiazolopyrimidine Derivatives for Anticancer Evaluation, Phosphorus, Sulfur, and
Silicon and the Related Elements, 182:8, 1739-1756
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Phosphorus, Sulfur, and Silicon, 182:1739–1756, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701313912
A Novel Synthesis of Some New Pyrimidine and
Thiazolopyrimidine Derivatives for Anticancer Evaluation
E. E. Flefel
M. A. Salama
M. El-Shahat
Photochemistry Department, National Research Centre, Dokki,
Cairo, Egypt
M. A. El-Hashash
Chemistry Department, Faculty of Science, Ain Shams University,
Abassia, Cairo, Egypt
A. F. El-Farargy
Chemistry Department, Faculty of Science, Zagazig University, Egypt
Diaryl-oxiran-2-yl methanones (2) were prepared and reacted with thiourea to
give 2-thioxo-tetrahydro-pyrimidine-5(2H)-ones (3).The latter compounds reacted
with bromoacetic acid to afford the title compounds (4). Also some new deriva-
tives were prepared from the reaction of compounds (3) and (4) with differ-
ent reagents. Compounds (3) were glycosidated with 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosylbromide (α-ABG) to afford the corresponding nucleosides.
Keywords 1,3-Diaryl-prop-2-en-1-ones; 1,3-diaryl-2,3-epoxypropanones; 4,6-diaryl-
hexahydro-2-thioxopyrimidin-5-ones; anticancer and antimicrobial activity
INTRODUCTION
Oxiranes (epoxides) are extremely reactive organic precursors that
can be used to synthesize several types of organic compounds.1−5
In previous work, the reaction of aryl methylenecycloalkanones with
thiourea to form biologically active pyrimidinethiones and thiazolones
was studied.6−8 In this article, we would like to report the use
Received October 31, 2006; accepted February 3, 2007.
Thanks to Dr. Seham Y. El-Tablawy, Lecturer at Pharmaceutical Microbiology Depart-
ment, National Centre for Radiation Research and Technology, Atomic Energy Authority,
Cairo, Egypt, for carrying out the in vitro antimicrobial activity.
Address correspondence to M.A. Salama, Photochemistry Department, National Re-
search Centre, Tahrir St., Dokki, Cairo D 12622, Egypt. E-mail: mowafsalam@yahoo.com
1739

1740
E. E. Flefel et al.
1,3-diaryl-2,3-epoxypropan-1-ones (2) for the synthesis of some hete-
rocyclic compounds and their biological evaluation.
RESULTS AND DISCUSSION
3-(4-Chloro-phenyl)-1-(3,4-dimethyl-phenyl)-propenone (1a) and 1-
(3,4-dimethyl-phenyl)-3-p-tolyl-propenone (1b)9 reacted with hydrogen
peroxide in alkaline medium to produce [3-(4-chloro-phenyl)-oxiranyl]-
(3,4-dimethyl-phenyl)-methanone (2a) and (3,4-dimethyl-phenyl)-(3-p-
tolyl-oxiranyl)-methanone (2b), respectively which have been utilized
as key starting materials in the synthesis of many interesting hete-
rocyclic compounds (Scheme 1). Analytical and spectral data of com-
pounds (2) are in total agreement with the proposed structure (c.f.
Experimental Section). Compounds (2), as a typical epoxides, reacted
with thiourea in alcoholic potassium hydroxide solution to pro-
duce 4-(4-chloro-phenyl)-6-(3,4-dimethyl-phenyl)-2-thioxo-tetrahydro-
pyrimidin-5-one (3a) and 4-(3,4-dimethyl-phenyl)-2-thioxo-6-p-tolyl-
tetrahydro-pyrimidin-5-one (3b). The reaction possible takes place via
the following (Figure 1).
Compounds (3) showed corrected value in elemental analysis as well
as compatible IR spectral data. 1H NMR spectrum (DMSO-d6) of com-
pound (3b) as an example showed the expected signals corresponding
to the aromatic protons and two types of exchangeable protons corre-
sponding to two types of NH groups, besides two doublets appear at
δ 3.006 and 3.386 ppm, each corresponds to a pyrimidine protons.13C
NMR spectrum of compound (3b) showed the expected signals for C O
at 181.411, C S at 175.891, aromatic carbons at 122.792–136.506, and
two signals in the SP3 carbon region at 42.892 and 71.480. The appear-
ance of the latter signals in 13C NMR spectrum and the two signals at δ
3.006 and 3.386 ppm in 1H NMR spectrum of compound (3b) suggests
that the produced pyrimidine ring is in fact alicyclic not aromatic and
be in twist boat form, in which the oxirane nucleus undergoes hetero
ring opening by thiourea at β-carbon followed by 1,2-hydride shift and
proton transfer affording the fleeting intermediate (A). The latter un-
dergoes ring closure to give the desired products (3). The two protons
at C-4 and C-6 can undergo long rang coupling and they both appear
as doublets. Compounds (3a) and (3b) are colorless (this ruled out thio-
quinone structure).
In the twist boat, the observed Raman spectrum of 1,4-
cyclohexanedione showed seven bands, all which showed coincidences
in the infrared) (Figure 2).10 That so many coincidences are highly im-
probable to be accidental, but it rather suggests that the compound has
the twist boat and not the chair.

Pyrimidine and Thiazolopyrimidine Derivatives
1741
SCHEME 1
Heating compounds under reflux (3) with bromoacetic acid
in acetic acid/acetic anhydride mixture in the presence of fused
anhydrous sodium acetate produced 5-(4-chloro-phenyl)-7-(3,4-
dimethyl-phenyl)-tetrahydro-7H-thiazolo[3,2-a]pyrimidine-3,6-dione

1742
E. E. Flefel et al.
FIGURE 1 Mechanism of formation of compounds (3).
(4a) and 7-(3,4-dimethyl-phenyl)-5-p-tolyl-tetrahydro-7H-thiazolo[3,2-
a]pyrimidine-3,6-dione (4b), rather than their isomer (4ꢀ)11 (Scheme 1).
Compounds (4) gave corrected value in elemental analysis besides dis-
playing the expected carbonyl absorption bands in the IR spectra (c.f.,
Experimental section). The two protons at C-2 are clearly magnetically
non-equivalent and they suffer from geminal coupling which led to the
appearance of two doublets at δ 4.457 and 4.568 ppm.
Similarly, compounds (3) reacted with 2-bromopropionic acid, under
the same reaction conditions to produce 5-(4-chloro-phenyl)-7-(3,4-
dimethyl-phenyl)-2-methyl-tetrahydro-7H-thiazolo[3,2-a]pyrimidine-
FIGURE 2 Twist boat form of compounds (3).

Pyrimidine and Thiazolopyrimidine Derivatives
1743
3,6-dione (5a) (Scheme 1). The latter compounds were prepared by new
method in which 2-bromopropionic acid was used as a cyclocondensa-
tion reagent in dioxane.12 This method is very easy to give compounds
identical in all aspects with compound (5a). Elemental analysis of
compound (5a) as well as its spectral data is compatible with the
proposed structures (c.f., Experimental section).
The presence of an active methylene group in compounds (4) could
be confirmed by condensation with aldehyde in acetic acid/acetic an-
hydride mixture in the presence of anhydrous sodium acetate to pro-
duce 7-(3,4-dimethyl-phenyl)-5-aryl-2-[aryl-methylidene]-tetrahydro-
7H-thiazolo[3,2-a]pyrimidine-3,6-diones (6) (Scheme 1). Compounds (6)
gave agreeable data in elemental analysis and spectral data (c.f., Exper-
imental section). Compounds (6) could be directly prepared from com-
pounds (3) in one step. Thus heating compound (3a) with bromoacetic
acid and aromatic aldehyde in acetic acid/acetic anhydride mixture in
the presence of sodium acetate gave product identical in all aspects with
compound (6a) ( m.p., mixed m.p., IR, MS, and 1H NMR).
Compounds (3) are present in equilibrium with their 2-mercapto
tautomers; they are expected to yield a mixture of two types of products
when alkylated, but under experimental condition of Mannich, we
could isolate only the 3-substituted product which proved to pos-
sess structure of compounds (7). Thus compounds (3) reacted with
formaldehyde in the presence of piperidine to give the corresponding
Mannich bases namely 6-(4-chloro-phenyl)-4-(3,4-dimethyl-phenyl)-
1-piperidin-1-ylmethyl-2-thioxo-tetrahydro-pyrimidin-5-one (7a) and
4-(3,4-dimethyl-phenyl)-1-piperidin-1-ylmethyl-2-thioxo-6-p-tolyl-
tetrahydro-pyrimidin-5-one (7b) successively (Scheme 1). The site of
1
the attack was reached by the study of the IR as well as the H NMR
and mass spectrum. Thus the IR spectrum of compound (7b) showed
the characteristic absorption bands at 1719.8, 1262.6, and 3293.4 for
C O, C S, and NH groups successively. Its mass spectrum showed
the molecular ion peak at m/z 422 (3.3%) supporting its molecular
1
formula, and H NMR spectrum agreed with the proposed structure
(c.f., Experimental section).
Additionally, when compound (3a) were glycosidated by coupling
with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide (α-ABG) in the
presence of triethyl amine, it gave 4-(4-chloro-phenyl)-6-(3,4-dimethyl-
phenyl)-1,3-di-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-thioxo-te-
trahydro-pyrimidin-5-one (8a) (Scheme 1), as the only isolable one
product as judged by Tlc analysis. The structure of the new product was
established according to its microanalytical and spectroscopic data. Its
IR spectrum reveals the disappearance of (2 NH groups) as well as the
existence of (C S group) at 1225.6 cm−1 (c.f. Experimental section).

1744
E. E. Flefel et al.
Compound (4a) coupled with aryldiazonium salt in pyridine
to give 7-(3,4- dimethyl-phenyl)-5-(4-chloro-phenyl)-2-(4-nitrophenyl-
hydrazono)-tetrahydro-7H-thiazolo [3,2-a]pyrimidine-3,6-dione (9a)
(Scheme 2). Compound (9a) gave corrected value in elemental anal-
ysis as well as compatible spectroscopic data (c.f., Experimental
section).
SCHEME 2

Pyrimidine and Thiazolopyrimidine Derivatives
1745
Interaction of compound (4a) with hydrazine hydrate afforded a prod-
uct its MS revealed two compounds one has m/z (M+ = 414) attributed
to (10a) and the other compound has m/z (M+ = 475) attributed to
(10b) in which hydrazine hydrate reacted with (10a) via addition and
condensation reactions. Further purification using colum chromatog-
raphy, we could isolate only (10a) as pure compound. The structure of
the new product was established according to its microanalytical and
spectroscopic data (Scheme 2) (c.f., Experimental section).
Also compound (4b) reacted with formaldehyde in the presence
of piperidine to give 7-(3, 4-dimethyl-phenyl)-2-piperidin-1-ylmethyl-
5-p-tolyl-tetrahydro-7H- thiazolo [3,2-a]pyrimidine-3,6-dione (11b)
(Scheme 2). Elemental analysis of compound (11b) as well as its
spectroscopic data is compatible with the proposed structure (c.f.
Experimental section).
ANTICANCER EVALUATION
Five selected new compounds (3a), (3b), (6a), (6b), and (6c) were tested
for cytotoxic activity against the MCF7 (Breast Carcinoma Cell Line)
and H460 (Lung Carcinoma Cell Line). All tested new compounds were
dissolved in DMSO in different concentrations (0, 1, 2, 5, and 10 µg/ml).
Preliminary experiments were made using the human tumour cell
line to identify the cytotoxicity of the selected compounds according
to Skehan et al.13
Measurement of Potential Cytotoxicity by Sulforhodamine B.
(SRB) Assay
Cells were plated in 96 multiwell plates (104 cells/ well) for 24 h
before treatment with the compounds to allow attachment of cell to
the wall of the plate.
Different concentrations of the compounds (1, 2.5, 5, and 10 µg/ml)
were added to the cell monolayer.
r
r
r
Triplicate wells were prepared for each individual dose.
Monolayer cells were incubated with the compounds for 48 h at 37◦C
r
and in atmosphere of 5% CO2.
After 48 h, cells were fixed, washed and stained with SRB stain.
Excess stain was washed with acetic acid and attached stain was
recovered with tris EDTA buffer.
Color intensity was measured in an ELISA Reader.
The relation between surviving fraction and drug concentrations was
r
r
r
r
plotted to get the survival curve of each tumor cell line of the specified
compound Skehan et al.13

1746
E. E. Flefel et al.
Results
All tested compounds were proven to have no cytotoxic activity (not
active) against the MCF7 and H460 at the chosen drug concentrations;
see Chart 1 and 2, respectively.
CHART 1

Pyrimidine and Thiazolopyrimidine Derivatives
1747
CHART 2
*The new compounds tested for anticancer activity in the Cairo Uni-
versity, National Cancer Institute, Cancer Biology Department, Cairo,
Egypt.
BIOLOGICAL EVALUATION
Antibacterial Activity
Result of the minimum inhibitory concentration (MIC) test against
Escherichia coli (Gram-negative bacteria) were not very promising,

1748
E. E. Flefel et al.
compound (6c) out of 12 compounds displayed MIC in range of about
90 µg/ml, while the other tested compounds were generally inefficient
(MIC >100 µg/ml) for each of bacteria and fungi.
Antifungal Activity
The prepared compounds 12 were evaluated in vitro against two strains
of fungi, Candida albicans and Aspergillus fumigates, the most clini-
cally fungi responsible for the majority of systemic fungi infections.
Result of (MIC) test against Aspergillus fumigates were not very
promising, one compound out of 12 displayed MIC in range of about
50 µg/ml, while the rest of the series were generally inefficient (MIC
>100 µg/ml).
Also, the result of (MIC) test against Candida albicans were not very
promising, two compounds out of 12 displayed MIC in range of about
20 µg/ml, while the rest of the series were generally inefficient (MIC
>100 µg/ml).
The different concentrations are produced by dilution (using the se-
rial discontinuous concentration method). The MIC was readed as the
smallest concentration of tested compound or control in series that pre-
vent the development of visible growth of the test organism.14 The MIC
values (µg/ml) of tested compounds together with their structures are
illustrated in Table I.
TABLE I In Vitro Antimicrobial Activity (MIC)
of Tested Compounds
Microorganism
Tested compounds Eschericha Aspergillus Candida
and references
coli
fumigates
albicans
Colimex
Floconazole
1µg/ml
—
>100
—
>100
—
2a
2b
3a
3b
4a
4b
6a
6b
6c
>100
>100
>100
>100
>100
>100
>100
>100
90
>100
>100
>100
>100
50
>100
> 100
>100
>100
>100
>100
>100
>100
>100
>100
>100
20
>100
>100
>100
>100
>100
20
7b
9a
11b
>100
>100
>100
>100

Pyrimidine and Thiazolopyrimidine Derivatives
1749
CONCLUSION
The tested compounds were evaluated in vitro against one strains of
Gram-negative bacteria (Escherichia coli.) and two strains of fungi, As-
pergillus fumigates and Candida albicans, Colimex, and Floconazole
were used as references. Compound (6c) exerted significant antibac-
terial activity against Escherichia coli in range of 90 µg/ml while the
rest of the compounds were generally inefficient (MIC >100 µg/ml).
On the other hand, compound (4a) showed antifungal activity against
Aspergillus fumigates in range of 50 µg/ml. Also compounds (4a) and
(9a) exerted significant antifungal activity against Candida albicans
in range of 20 µg/ml, while the rest of the compounds were generally
inefficient (MIC >100 µg/ml) against each ofAspergillus fumigates and
Candida albicans.
EXPERIMENTAL
All melting points are uncorrected and were measured using an Elec-
trothermal IA 9100 apparatus. Analytical data were performed by Vario
El Mentar apparatus, organic microanalysis section, National Research
Centre. Their results were found to be in agreement with the calculated
values ( 0.5). The IR spectra (KBr) were recorded on a Pye Unicam Sp-
3-300 and Shimadzu FTIR 8101 PC infrared spectrophotometer. The
NMR spectra were recorded on a Varian Mercury VX-300 NMR spec-
1
trometer. H spectra were run at 300 MHz and 13C spectra were run
at 75.46 MHz in dimethylsulphoxide (DMSO-d6). Chemical shifts are
quoted in δ and were related to that of the solvents. The Mass spectra
were recorded on a Shimadzu GCMS-QP-1000EX mass spectrometer
at 70 ev.
Compound 1 was prepared according to method reported in
literature.9
[3-(4-Chloro-phenyl)-oxiranyl]-(3,4-dimethyl-phenyl)-
methanone (2a)
Hydrogen peroxide (5 ml, 30%) was added portion wise to a mixture of
3-(4-chloro-phenyl)-1-(3,4-dimethyl-phenyl)-propenone (1a) (0.01 mol)
in acetone (50 ml), and methanol (15 ml) containing NaOH (1 g) at
20–25◦C with stirring. The reaction mixture was left over night, cold
water was added and the precipitated solid was filtered off, washed with
cold water and crystallized from ethanol to give compound (2a) in 85%
yield; m.p 96–97◦C. IR spectrum (KBr, ν, cm−1): 1655 (C O); 1H NMR
spectrum (DMSO-d6, δ ppm): 2.27 (s, 3H, CH3), 2.24 (s, 3H, CH3), 4.13

1750
E. E. Flefel et al.
(s, 1H, epoxy-H), 4.80 (s, 1H, epoxy-H), 7.300–7.780 (m, 7 H, Ar-H); MS,
m/z (%): 286 (M+, 41.02), 133 (100). Analysis for C17H15O2Cl (286.5):
required C, 71.20; H, 5.27; found C, 71.22; H, 5.29.
(3,4-Dimethyl-phenyl)-(3-p-tolyl-oxiranyl)-methanone (2b)
Hydrogen peroxide (5 ml, 30%) was added portion wise to a mixture of
1-(3,4-dimethyl-phenyl)-3-p-tolyl-propenone (1b) (0.01 mol) in acetone
(50 ml), and methanol (15 ml) containing NaOH (1 g) at 20–25◦C with
stirring. The reaction mixture was left over night, cold water was added,
and the precipitated solid was filtered off, washed with cold water, and
crystallized from ethanol to give compound (2b) in 80% yield; m.p. 80◦C
IR spectrum (KBr, ν, cm−1): 1724.7 (C O); MS, m/z (%): 266 (M+, 53.25),
242 (100). Analysis for C18H18O2 (266): required C, 81.17; H, 6.81; found
C, 81.30; H, 6.77.
Synthesis of (3a) and (3b)
A mixture of compounds (2) (0.01 mol) and thiourea (0.01 mol) in
ethanolic potassium hydroxide (2 g in 100 ml ethanol) was refluxed
for 4 h. The solvent was evaporated and the formed precipitate was
washed several time with acidified cold water filtered off and recrystal-
lized from the proper solvent to give compounds (3a) and (3b).
4-(4-Chloro-phenyl)-6-(3,4-dimethyl-phenyl)-2-thioxo-
tetrahydro-pyrimidin-5-one (3a)
From acetic acid, yield 72%, m.p. 137◦C. IR spectrum (KBr, ν, cm−1):
3128 (2NH), 1245.7 (C S), 1757 (C O);1H NMR spectrum (DMSO-d6,
δ ppm): 2.22 (s, 3H, CH3), 2.25 (s, 3H, CH3), 3.047 (d, 1H, pyrimidine-
H), 3.493 (d, 1H, pyrimidine-H), 7.187–7.377 (m, 7 H, Ar-H ), 10.663
(s, 1H, NH, D2O exchangeable), 11.478 (s, 1H, NH, D2O exchangeable);
MS, m/z (%): 344 (M+, 13.23), 132 (100). Analysis for C18H17N2OSCl
(344.5): required C, 62.69; H, 4.97; N, 8.12; S, 9.28; found C, 62.70; H,
4.98; N, 8.11; S, 9.01.
4-(3,4-Dimethyl-phenyl)-2-thioxo-6-p-tolyl-tetrahydro-
pyrimidin-5-one (3b)
From benzene, yield 68%; m.p. 170◦C. IR spectrum (KBr, ν, cm−1): 3292,
3181 (2NH), 1263.5 (C S), 1725 (C O);1H NMR spectrum (DMSO-d6,
δ ppm): 2.22 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.006
(d, 1H, pyrimidine-H), 3.386 (d, 1H, pyrimidine-H), 7.068–7.359 (m,
7H, Ar-H ), 10.638 (s, 1H, NH, D2O exchangeable), 11.378 (s, 1H, NH,
D2O exchangeable);13C-NMR spectrum (DMSO-d6, δ ppm): 42.892 and

Pyrimidine and Thiazolopyrimidine Derivatives
1751
71.480 SP3 carbon, 122.792–136.506 aromatic carbons, 175.891 C S,
181.417 C O. MS, m/z (%): 324 (M+, 38.9), 219 (100). Analysis for
C19H20N2OS (324): required C, 70.34; H, 6.25; N, 8.63; S, 9.88; found C,
70.30; H, 6.25; N, 8.50; S, 9.50.
Synthesis of (4a) and (4b)
Method A
A mixture of compounds (3) (0.01 mol) with bromoacetic acid (0.01
mole) in acetic acid (30 ml)/acetic anhydride (15 ml) mixture in the pres-
ence of fused anhydrous sodium acetate (2 g) was refluxed for 3 h. The
solution was cooled, gradually poured onto cold water and the formed
precipitate was washed several times with water, filtered off and re-
crystallized from acetic acid to give compounds (4a) and (4b).
Method B
A mixture of compounds (3) (0.01 mol) with bromoacetic acid
(0.01 mol) in dioxane was refluxed for 3 h. The solvent was evaporated
and the formed precipitate was filtered off and recrystallized from acetic
acid to give compounds identical in all aspects with compounds obtained
from method A.
5-(4-Chloro-phenyl)-7-(3,4-dimethyl-phenyl)-tetrahydro-7H-
thiazolo[3,2-a]pyrimidine-3,6-dione (4a)
Yield 65%; m.p. 146◦C. IR spectrum (KBr, ν, cm−1): 1720 (C O),
1743(C O);1H NMR spectrum (DMSO-d6, δ ppm): 2.21 (s, 3H, CH3),
2.24 (s, 3H, CH3), 3.549 (d, 1H, pyrimidine-H), 3.749 (d, 1H, pyrimidine-
H), 4.457 (d, 1H, thiazole-H), 4.568 (d, 1H, thiazole-H), 6.935–7.665
(m, 7H, Ar-H ); MS, m/z (%): 384 (M+, 19.61), 132 (100). Analysis for
C20H17N2O2SCl (384.5): required C, 62.41; H, 4.45; N, 7.28; S, 8.33;
found C, 62.50; H, 4.60; N, 7.20; S, 8.20.
7-(3,4-Dimethyl-phenyl)-5-p-tolyl-tetrahydro-7H-thiazolo
[3,2-a]pyrimidine-3,6-dione (4b)
Yield 62%; m.p. 185◦C. IR spectrum (KBr, ν, cm−1): 1720 (C O),
1740(C O);Analysis for C21H20N2O2S (364): required C, 69.21; H, 5.53;
N, 7.69; S, 8.30; found C, 68.90; H, 5.54; N, 7.70; S, 8.38.
Synthesis of (5a)
Method A
A mixture of compound (3a) (0.01 mol) with 2-bromopropionic acid
(0.01 mol) in acetic acid (30 ml)/acetic anhydride (15 ml) mixture in

1752
E. E. Flefel et al.
the presence of fused anhydrous sodium acetate (2 g) was refluxed
for 3 h. The solution was cooled, gradually poured onto cold wa-
ter, and the formed precipitate was washed several times with wa-
ter, filtered off, and recrystallized from ethanol to give compound
(5a).
Method B
A mixture of compound (3a) (0.01 mole) with 2-bromopropionic acid
(0.01 mole) in dioxane was refluxed for 3 h. The solvent was evaporated,
and the formed precipitate was filtered off and recrystallized from acetic
acid to give compound identical in all aspects with compound obtained
from method A.
5-(4-Chloro-phenyl)-7-(3,4-dimethyl-phenyl)-2-methyl-
tetrahydro-7H-thiazolo[3,2-a]pyrimidine-3,6-dione (5a)
Yield 63%; m.p. 132◦C. IR spectrum (KBr, ν, cm−1): 1700 (C O), 1756.5
(C O); 1H NMR spectrum (DMSO-d6, δ ppm): 1.604 (d, 3H, CH3), 2.238
(s, 3H, CH3), 2.247 (s, 3H, CH3), 3.058 (d, 1H, pyrimidine-H-7), 3.416
(d, 1H, pyrimidine-H-5), 4.441 (q, 1H, thiazole-H), 7.097–7.332 (m,
7H, Ar-H ); MS, m/z (%): 383 (M+-15, 23.99), 125 (100). Analysis for
C21H19N2O2SCl (398.5): required C, 63.23; H, 4.87; N, 7.18; S, 8.03;
found C, 63.22; H, 4.77; N, 7.17; S, 8.00.
Synthesis of (6a–c)
Method A
A mixture of compounds (4) (0.01 mole) and equimolar amount
of the corresponding aromatic aldehyde in acetic anhydride (30
ml) was refluxed for 3 h. The solution was cooled, gradually
poured onto cold water and the formed precipitate was filtered
off and recrystallized from the proper solvent to give compounds
(6a–c).
Method B
A mixture of compounds (3) (0.01 mol), bromoacetic acid (0.01 mol),
equimolar amount of the corresponding aromatic aldehyde in acetic
acid (30 ml)/acetic anhydride (15 ml) mixture in the presence of fused
anhydrous sodium acetate (2 g) was refluxed for 3 h. The solution was
cooled, gradually poured onto cold water and the formed precipitate
was washed several times with water, filtered off, and recrystallized
from the proper solvent to give compounds identical in all aspects with
compounds obtained from method A.

Pyrimidine and Thiazolopyrimidine Derivatives
1753
5-(4-Chloro-phenyl)-7-(3,4-dimethyl-phenyl)-2-[4-floro-
phenyl-methylidene]-tetrahydro-7H-thiazolo [3,2-a]
pyrimidine-3,6-dione (6a)
From: benzene/pet. ether, yield 73%; m.p. 190◦C. IR spectrum (KBr,
ν, cm−1): 1702.7 (C O), 1737.3 (C O); Analysis for C27H20FN2O2SClF
(490.5): required C, 66.05; H, 4.07; N, 5.70; S, 6.52; found C, 66.05; H,
4.07; N, 5.75; S, 6.60.
7-(3,4-Dimethyl-phenyl)-5-p-tolyl-2-[4-methoxy-phenyl-
methylidene]-tetrahydro-7H-thiazolo[3,2-a]-
pyrimidine-3,6-dione (6b)
From: pet. Ether as an eluent on silica gel column chromatography,
yield 60%; oil. IR spectrum (KBr, ν, cm−1): 1703 (C O), 1757.4 (C O);
1H NMR spectrum (DMSO-d6, δ ppm): 2.215 (s, 3H, CH3), 2.245 (s, 3H,
CH3), 2.309 (s, 3H, CH3), 3.549 (d, 1H, pyrimidine-H), 3.749 (d, 1H,
pyrimidine-H), 3.908 (s, 3H, OCH3), 6.935–7.665 (m, 7H, Ar-H ), 9.974
(s, 1H, exocyclic vinylic-H);15 MS, m/z (%): 482 (M+, 75.14), 105 (100).
Analysis for C29H26N2O3S (482): required C, 79.45; H, 5.43; N, 6.34; S,
7.30; found C, 79.55; H, 5.66; N, 6.29; S, 7.30.
7-(3,4-Dimethyl-phenyl)-5-p-tolyl-2-[4-floro-phenyl-
methylidene]-tetrahydro-7H-thiazolo[3,2-a]-
pyrimidine-3,6-dione (6c)
From: benzene/pet. ether, yield 68%; m.p. 210◦C. IR spectrum (KBr, ν,
cm−1): 1700 (C O), 1726.2 (C O); MS, m/z (%): 456 (M+-14, 3); Analysis
for C28H23N2O2SF (470): required C, 71.64; H, 4.90; N, 5.97; S, 6.83;
found C, 71.54; H, 4.70; N, 5.23; S, 6.45.
Synthesis of (7a) and (7b)
Formaldehyde (1 ml, 40%) was added to compounds (3) (0.01 mol) in
anhydrous ethanol (30 ml) the reaction mixture was heated for 5 min-
utes, then piperidine (0.01 mole) was added to the cold solution and the
reaction mixture was stirred for 3 h at room temperature. The formed
solid filtered off and recrystallized from ethanol to give compounds (7a)
and (7b).
6-(4-Chloro-phenyl)-4-(3,4-dimethyl-phenyl)-1-piperidin-1-
ylmethyl-2-thioxo-tetrahydro-pyrimidine-5-one (7a)
Yield 83%; m.p. 215◦C. IR spectrum (KBr, ν, cm−1): 3279.3 (NH), 1287.3
(C S), 1723.9 (C O);1H NMR spectrum (DMSO-d6, δ ppm): 1.201–
1.458 (m, 6H, piperidine-H), 1.974 (t, 4H, piperidine-H ), 2.216 (s, 3H,

1754
E. E. Flefel et al.
CH3), 2.249 (s, 3H, CH3), 3.105 (d, 1H, pyrimidine-H), 3.489 (d, 1H,
pyrimidine-H), 4.181 (d, 1H, CH2), 4.57 (d, 1H, CH2), 7.183–7.378 (m,
7H, Ar-H ), 10.99 (s, 1H, NH, D2O exchangeable). MS, m/z (%): 441 (M+,
1.5), 98 (100). Analysis for C24H28N3OSCl (441): required C, 65.21; H,
6.38; N,9.51; S, 7.25; found C, 65.30; H, 6.40; N,9.70; S, 7.30.
4-(3,4-Dimethyl-phenyl)-1-piperidin-1-ylmethyl-2-thioxo-6-p-
tolyl-tetrahydro-pyrimidin-5-one (7b)
Yield 79%; m.p. 205◦C. IR spectrum (KBr, ν, cm−1): 3293 (NH), 1283.5
(C S), 1719 (C O);1H NMR spectrum (DMSO-d6, δ ppm): 1.097–1.246
(m, 6H, piperidine-H), 1.980 (t, 4H, piperidine-H ), 2.214 (s, 3H, CH3),
2.38 (s, 3H, CH3), 2.247(s, 3H, CH3), 3.058 (d, 1H, pyrimidine-H), 3.416
(d, 1H, pyrimidine-H), 4.212 (d, 1H, CH2), 4.441 (d, 1H, CH2), 7.097–
7.332 (m, 7H, Ar-H ). MS, m/z (%): 422 (M++ 3.1), 98 (100). Analysis for
C25H31N3OS (421): required C, 71.42; H, 7.38; N, 6.66; S, 7.61; found,
71.44; H, 7.40; N, 6.72; S, 7.66.
4-(4-Chloro-phenyl)-6-(3,4-dimethyl-phenyl)-1,3-di-(2,3,4,6-
tetra-O-acetyl-β-D-glucopyranosyl)-2-thioxo-tetrahydro-
pyrimidin-5-one (8a)
To a solution of compound (3a) (0.01 mol) in 1 ml triethylamine, a solu-
tion of 2,3,4,6-tetra-O-acetyl-α-glucopyranosyl bromide (0.02 mol) in 5
ml DMF was added then the reaction mixture was stirred for 8 h at room
temperature, evaporated under reduced pressure at 40◦C, the residue
washed with distilled water, filtered off, dried to afford an oily prod-
uct compound (8a), IR spectrum (KBr, ν, cm−1): 1658 (C O) and 1747
(C O).1H NMR spectrum (DMSO-d6, δ ppm):1.980, 2.000, 2.023, 2.037,
2.050, 2.070, 2.082, 2.098 (8s, 24H, 8CH3CO- ), 2.223 (s, 3H, CH3), 2.258
(s, 3H, CH3), 3.047 (d, 1H, pyrimidine-H), 3.448 (d, 1H, pyrimidine-H) ,
4.139-4.210 (m, 6H, 5ꢀ-H, 5ꢀꢀ-H, 6ꢀ-H2 , 6ꢀꢀ-H2), 4.742-4.923 (m, 7H, 2ꢀ-H,
2ꢀꢀ-H, 3ꢀ-H, 3ꢀꢀ-H, 4ꢀ-H, 4ꢀꢀ-H, 1ꢀ-H), and 5.446 (d, 1H, 1ꢀꢀ-H).16
5-(4-Chloro-phenyl)-7-(3,4-dimethyl-phenyl)-2-(4-nitrophenyl-
hydrazono)-tetrahydro-7H-thiazolo [3,2-a]pyrimidin-3,6-
dione (9a)
The aromatic amine (0.01 mol) was dissolved in concentrated hydrochlo-
ric acid (3 ml) and water (2 ml) cooled to −10◦C and treated with sodium
nitrate (0.7 g, 5 ml water). The diazotized amine was added gradually
while stirring to cooled solution of compound (4a) (0.01 mol) in pyri-
dine (20 ml). The reaction mixture was refrigerator for 1/2 h and then

Pyrimidine and Thiazolopyrimidine Derivatives
1755
diluted with water and recrystallized from benzene/pet. ether to give
compound (9a) in 52% yield; m.p. 152◦C. IR spectrum (KBr, ν, cm−1):
3296.6 (NH), 1705 (C O), 1771.4 (C O);1H NMR spectrum (DMSO-d6,
δ ppm): 2.238 (s, 3H, CH3), 2.247 (s, 3H, CH3), 3.058 (d, 1H, pyrimidine-
H), 3.416 (d, 1H, pyrimidine-H) , 3.831 (s, 1H, NH, D2O exchangeable),
7.097–7.332 (m, 11 H, Ar-H ); MS, m/z (%): 533 (M+, 40.7), 132 (100).
Analysis for C26H20N5O2SCl (533): C, 61.25; H, 4.59; N, 10.20; S, 5.84;
found C, 61.00; H, 4.62; N, 10.22; S, 5.85.
4-(4-Chloro-phenyl)-6-(3,4-dimethyl-phenyl)-5,6-
dihydropyrimidin-2-yl-thioacetylhydrazide (10a)
To a solution of compound (4a) (0.05 mol) in absolute ethanol (15 ml),
hydrazine hydrate (98%) (0.06 mol) was added and the reaction mix-
ture was refluxed for 2 h. The reaction mixture was cooled, poured into
water, and the solid product formed was washed with little ethanol,
filtered off, and chromatographed on silica gel column using pet. ether
(60–80) as an eluent to give compound (10a) in 50% yield; m.p 196◦C.
IR spectrum (KBr, ν, cm−1): 3286.3 (br NHNH2), 1720.9 (C O), 1651.1
(C O);1H NMR spectrum (DMSO-d6, δ ppm): 2.223 (s, 3H, CH3), 2.258
(s, 3H, CH3), 3.047 (d, 1H, pyrimidine-H), 4.386 (s, 2H, NH2, D2O ex-
changeable), 5.139 (s, 2H, CH2), 7.187–7.377 (m, 7H, Ar-H ), 12.379
(s, 1H, NH, D2O exchangeable). Analysis for C20H19N4O2SCl (414): C,
57.97; H, 4.58; N, 13.52; S, 7.72; found C, 57.23; H, 4.33; N, 13.09; S,
7.60.
7-(3,4-Dimethyl-phenyl)-2-piperidin-1-ylmethyl-5-p-tolyl-
tetrahydro-7H-thiazolo[3,2-a]pyrimidine-3,6-dione (11b)
Formaldehyde (1 ml, 40%) was added to compound (4b) (0.01 mol) in an-
hydrous ethanol (30 ml) the reaction mixture was heated for 5 minutes,
then piperidine (0.01 mol) was added to the cold solution and the reac-
tion mixture was stirred for 3 h at room temperature. The formed solid
filtered off and recrystallized from ethanol to give compound (11b) in
55% yield; m.p. 210◦C. IR spectrum (KBr, ν, cm−1):1500.5 (C N), 1705
(C O), 1771 (C O);1H NMR spectrum (DMSO-d6, δ ppm): 1.097–1.246
(m, 6H, piperidine-H), 1.980 (t, 4H, piperidine-H), 2.214 (s, 3H, CH3),
2.238 (s, 3H, CH3), 2.247 (s, 3H, CH3), 3.058 (d, 1H, pyrimidine-H), 3.416
(d, 1H, pyrimidine-H), 4.323–4.408 (m, 1H, CH2 ), 4.496–4.539 (m, 1H,
CH2), 5.030–5.120 (m, 1H, thiazole-H ), and 7.097–7.332 (m, 7 H, Ar-
H), MS, m/z (%): 406 (M+-55, 3.2), 98 (100). Analysis for C27H31N3O2S
(461): required C, 70.28; H, 6.72; N, 9.11; S, 6.94; found C, 70.00; H,
6.11; N, 9.00; S, 6.55.

1756
E. E. Flefel et al.
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