A facile synthesis and heteroannulation of thiazolopyrimidine and related heterocyclic systems

Article abstract of DOI:10.1002/jhet.5570450408

(Chemical Equation Presented) Reaction of pyrimidinylacetic acid 2 with different electrophilic and nucleophilic reagents gave annulated pyrimidine derivatives 3-11, respectively. Compound 3 was transformed to pyrimidinylacetyl azide 12, which upon hetero

Full text of DOI:10.1002/jhet.5570450408

Jul-Aug 2008
993
A Facile Synthesis and Heteroannulation of Thiazolopyrimidine and
Related Heterocyclic Systems
A. A. Aly
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
E-mail:alymaboud@yahoo.com
Received April 3, 2007
O
CH2(COOEt)2
N
N
N
Ar`CH2C
O
O
Ph
N
COOEt
16
CH2C N3
N
Ar
S
Ph
O
N
N
12
PhNCO
CH2Ar`
O
17
Reaction of pyrimidinylacetic acid 2 with different electrophilic and nucleophilic reagents gave
annulated pyrimidine derivatives 3-11, respectively. Compound 3 was transformed to pyrimidinylacetyl
azide 12, which upon heterocyclization with active methylene compounds, acidic and basic reagents
furnished functionally substituted heteroaromatic compounds 13-21, respectively. The antimicrobial
activity of some synthesized compounds was investigated. The structures of the synthesized derivatives
were elucidated by elemental and spectral analyses.
J. Heterocyclic Chem., 45, 993 (2008).
INTRODUCTION
3410-3260 due to ꢀ(OH, NH) and at 1695 cm-1 for ꢀCO.
The H NMR (CDCl3) spectrum showed signals at ꢁ
1
Pyrimidine derivatives and heterocyclic annulated
pryimidine are well known in medicinal chemistry for
their pronounced therapeutic applications [1-5] such as
inhibitors of HIV-1 integrase, CNS stimulants, protein
kinase inhibitors and anticancer drugs. Non-medicinal
applications [6-10] include uses as herbicides,
agricultural fungicides, growth promoters and UV
absorbing molecules. One possible reason for their
activity is the presence of pyrimidine base in thymine,
cytosine and uracil which are essential building blocks
of nucleic acids, DNA and RNA. Our studies [11-13]
related to synthesis of annulated pyrimidines for testing
as potential biodegradable agrochemical and antimi-
crobial agents by the functionalization and cyclization
reactions of [4-(dibenzothien-2-yl)-2-mercapto-6-
phenyl-1,6-dihydropyrimidin-5-yl]acetic acid (2) with
different reagents.
2.95 ppm for methylene protons, singlet at 4.63 for
methine proton, multiplet signals (12 H) for aromatic
protons at (7.11-7.95) ppm, two broad singlets at (8.40-
8.60) ppm for two NH and singlet at 10.61 ppm for OH,
which disappeared upon addition of D2O to the NMR
sample. Also, the mass spectrum of 2 revealed a
molecular ion peak at m/z = 430 which corresponding
to molecular formula C24H18N2O2S2.
Pyrimidinylacetic acid 2 used as a versatile inter-
mediate allowing access for preparation of a variety of
multifunctionalized polyheterocycles, due to the presence
of two adjacent reactive functional groups. Thus, the
reaction of 2 with 1,2-dibromoethane afforded [7-
(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo-
[3,2-a]pyrimidin-6-yl]acetic acid (3). While, the
condensation of 2 with 1,3-dibromopropane yielded the
corresponding pyrimido[2,1-b][1,3]thiazine derivative 4
(Scheme 1).
RESULTS AND DISCUSSION
The preparative use of pyrimidinylacetic acid 2 was
extended to prepare new annulated pyrimidine
derivatives. Thus, the alkylation of 2 with chloroacetic
acid in a mixture of glacial acetic acid/acetic anhydride
containing anhydrous sodium acetate afforded [7-
(dibenzothien-2-yl)-3-oxo-5-phenyl-2,3-dihydro-5H-thia-
zolo[3,2-a]pyrimidin-6-yl]acetic acid (5), which
condensed with benzaldehyde to give the corresponding
benzylidene derivative 6, (Scheme 2).
The required starting material, [4-(dibenzothien-2-yl)-
2-mercapto-6-phenyl-1,6-dihydropyrimidin-5-yl]acetic
acid (2) was prepared from readily available 3-
[(dibenzothien-2-oyl)]propanoic acid (1), thiourea and
benzaldehyde in ethanolic solution containing
anhydrous potassium carbonate. The structure of
compound 2 was assigned on the basis of elemental
analysis and compatible spectroscopic data. Thus, its IR
spectrum showed characteristic absorption bands at

994
A.A. Aly
Vol 45
Scheme 1
amount of acrylonitrile in pyridine underwent a Michael-
type addition to the activated double bond of the nitrile to
afford the propionitrile derivative 8, which underwent
cyclization to pyrimidothiazine 9 by refluxing in a
mixture of glacial acetic acid and hydrochloric acid (3:1).
The condensation of compound 9 with benzaldehyde
afforded [3-benzylidene-8-(dibenzothien-2-yl)-2-oxo-6-
phenyl-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-7-
yl]acetic acid (10), which reacted with hydroxylamine
hydrochloride to give the cyclized tricyclic derivative 11,
(Scheme 2).
In recent years, there has been increasing interest in the
synthesis of alkyl azide, this stems from its applicability
for synthesis of polyfunctionally substituted heterocycles
[14-16]. Thus, thiazolopyrimidinylacetyl azide 12 was
synthesized following the reported method [17] by stirring
equimolar amounts of [7-(dibenzothien-2-yl)-5-phenyl-
2,3-dihydro-5H-thiazolo[3,2-b]pyrimidin-6-yl]acetyl
chloride and aqueous sodium azide in dry acetone at 0-5
°C, (Scheme 3).
Ph
S
O
HO
EtOH
NH
ArCCH2CH2COOH + H2NCNH2 + PhCHO
O
1
Ar
N
H
S
Ph
HO
BrCH2CH2Br
N
O
Ar
N
S
Ph
3
HO
NH
SH
O
Ar
N
Ph
HO
2
Br(CH2)3Br
N
O
Ar
N
S
4
Ar =
S
Scheme 2
Ph
N
Ph
N
To increase the synthetic scope on the utility of the
azide 12 as a building blocks for developing bioactive
triazole [18], oxadiazole [19], quinazoline [20]
derivatives. Accordingly, the cycloaddition reaction [21]
of alkyl azide 12 with active methylene compounds (viz
malononitrile, ethyl cyanoacetate, ethyl acetoacetate and
diethyl malonate) afforded the triazole derivatives 13-16,
respectively (Scheme 3). While, the cycloaddition
reaction of 12 with phenyl isocyanate in dry benzene
yielded,5-{[7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidin-6-yl]-methyl}-3-phenyl-1-
3,4-oxadiazol-2(3H)-one (17).
HO
HO
N
NH
SH
CH2=CHCN
O
O
CN
Ar
SH
Ar
8
2
ClCH2CO2H
Cyclization
Ph
Ph
HO
O
HO
N
N
O
O
Ar
N
S
O
Ar
N
S
5
9
PhCHO
PhCHO
Additionally, the reaction of azide 12 with glycolic acid
and/or thioglycolic acid in boiling dry benzene afforded
oxazolidine-2,4-dione and thiazolidine-2,4-dione 18a,b,
respectively, via Curtius rearrangement followed by 1,2-
dipolar addition and cyclization to give the desired
product. Moreover, azide 12 was shown to decompose
through azido-displacement pathway upon treatment with
glycine in dry toluene containing catalytic amount of
piperidine to give 2-{[7-(dibenzothien-2-yl)-5-phenyl-2,3-
dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl]-
Ph
Ph
HO
O
HO
N
CHPh
O
N
O
O
CHPh
Ar
N
S
Ar
N
S
6
10
H2NOH.HCl
H2NOH.HCl
Ph
Ph
O
HO
HO
N
NH
Ph
N
Ph
NH
O
methyl}oxazol-5(4H)-one (19).
O
Ar
N
S
Ar
N
S
O
Finally, the reaction of azide 12 with anthranilic acid
afforded disubstituted urea 20, which easily cyclized by
boiling in acetic anhydride to give the quinazoline
derivative 21, (Scheme 3).
7
11
Ar =
The structures of the synthesized compounds were
assigned on the basis of elemental analysis and spectral
data (cf. experimental).
S
Antimicrobial activity. The antimicrobial activity of
the synthesized compounds was tested in vitro using the
hole plate and filter paper disc methods [22]. All
compounds were tested for activity against Gram-positive
Compound 6 underwent cyclization into isoxazolothia-
zolopyrimidine derivative upon treatment with
hydroxylamine hydrochloride in refluxing pyridine.
7
Cyanoethylation of compound 2 with an equimolar

Jul-Aug 2008
A Facile Synthesis and Heteroannulation of Thiazolopyrimidine
995
Scheme 3
O
CH2(CN)2
Ar`CH
N
N
N
2C
H2N
CN
13
O
NCCH2COOEt
Ar`CH
N
N
N
2C
H2N
COOEt
14
O
CH3COCHCOOEt
N
N
N
Ar`CH2C
Ph
N
CH2COOH
Ar
H3C
15
N
COOEt
S
3
O
CH2(COOEt)2
N
N
N
Ar`CH2C
(i) SOCl2
(ii) NaN3
O
COOEt
16
Ph
O
CH2C N3
N
PhNCO
Ph
N
N
Ar
S
N
CH2Ar`
O
O
12
17
O
N-CH2Ar`
O
HXCH2CO2H
H2NCH2CO2H
X
18a,b
18a; X = O
18b; x = S
N
O
CH2Ar`
O
19
H2N
O
Ph
N
H
N
O
NHCNHCH2Ar`
HOOC
Ac2O
N
Ar`=
NCH2Ar`
COOH
S
O
20
S
21
and Gram-negative bacteria using streptomycin as a
reference standard drug. Based on the previous
preliminary test, the tested compounds were dissolved in
10 % acetone (v/v), and the selected concentrations are
(500, 250, 125 μg/mL). A qualitative screen was
performed on all compounds, while quantitative assays
were done on active compounds only. The results are
summarized in Table I. The results obtained from
microbiological screening of the synthesized compounds
showed highly antibacterial and moderate antifungal
activities comparable to that of streptomycin, the
reference drug used.
EXPERIMENTAL
Melting points are uncorrected. IR spectra in KBr were
recorded on a Perkin-Elmer 298 spectrophotometer. H and 13C
NMR spectra were obtained on a Varian Gemini 200 MHz
instrument using TMS as internal reference with chemical shifts
expressed as ꢀ ppm. Mass spectra were recorded on a Shimadzu
GCMS-QP 1000 instrument (70 eV El mode). 13C NMR values
of phenyl and dibenzothiophene groups for compounds 3-21 are
the same as in compound 2 with ꢀ ± 0.1-0.5 ppm.
[4-(Dibenzothien-2-yl)-2-mercapto-6-phenyl-1,6-dihydro-
pyrimidin-5-yl]acetic acid (2). A mixture of 3-[(dibenzothien-
2-oyl)]propanoic acid (1), (5.7 g, 20 mmol), thiourea (1.6 g, 20
mmol), benzaldehyde (2.1 mL, 20 mmol) and K2CO3 (2.8 g, 20
mmol) in ethanol (60 mL) was refluxed for 10 h. The reaction
mixture was cooled and the solid obtained was dissolved in hot
water. The filtrate was neutralized with acetic acid to give solid
product which was recrystallized from ethanol to give 2. Yield,
1
In conclusion, the described method seems to be very
useful for the synthesis of annulated pyrimidine
derivatives of potentially biologically active compounds
using the readily available pyrimidinylacetic acid.

996
A.A. Aly
Vol 45
Table I
The antimicrobial activity of the tested compounds.
Staphylococcus
aureus
Bacillus
cereus
Escherichia
coli
Pseudomon
aurignosa
Aspergillus
niger
Penicillium
italicum
Compound No
A
+
+
MIC
250
500
250
250
250
250
500
250
125
250
125
125
250
250
250
A
+
++
+
+++
+++
+
++
+++
++
++
++
++
++
+++
++
MIC
A
++
+
MIC
250
250
500
125
125
250
125
250
250
250
250
250
250
250
125
A
+
+
++
+
++
+
++
+
+
++
+++
+
MIC
250
125
250
250
125
125
500
250
250
125
250
125
125
125
125
A
MIC
500
125
250
-
A
-
-
-
+
-
MIC
-
-
2
3
5
7
9
10
11
13
15
16
17
18b
500
250
250
250
500
250
250
125
250
250
125
500
125
500
125
+
+
++
-
++
+++
++
++
+++
++
++
+++
++
++
++
++
++
+++
++
++
++
++
+++
++
++
+++
++
+
-
125
-
-
-
-
+
+
+
-
-
+
-
++
+
+
250
250
250
-
-
-
-
++
-
+
+
-
+
+
+
125
-
125
500
-
125
500
500
-
125
-
250
125
125
19
21
+
+
+++
++
++
Streptomycin
A = Antimicrobial activity of tested compounds; MIC = Minimum inhibitory concentration; -, inactive; + > 5mm, slightly active; ++ > 7
mm, moderately active; +++ > 9 mm, highly active
5.4 g (63%); mp 221-3 °C; IR: ꢀ = 3410-3260 (multiple bands
1
thiazine), 3.93 (s, 2H, CH2), 4.13 (s, 1H, methine), 7.29-8.11 (m,
12H, ArH), 10.71 (s, 1H, OH, exchangeable); Anal. Calcd for
C27H22N2O2S2 (470.61): C, 68.91; H, 4.71; N, 5.95%. Found: C,
68.80; H, 4.91; N, 5.83%.
OH, NH), 1695 (CO), 1265 cm-1 (CS); H NMR (CDCl3): ꢁ =
2.95 (s, 2H, CH2), 4.63 (s, 1H, methine), 7.11-7.95 (m, 12H,
ArH), 8.40-8.60 (br s, 2H, 2NH, exchangeable), 10.61 (s, 1H,
OH, exchangeable); Ms: m/z = 430 (M+): 13C NMR: ꢁ=26.8
(CH2),59.3(C-6),108.3(C-5), 136.3(C-4), 160.3(CO), 167.2(CS);
115.2, 115.8, 117.3, 118.2, 121.4, 126.3(C-of phenyl ring);
120.2, 120.8, 121.6, 122.2, 124.4, 124.9, 130.2, 130.9, 136.2,
137.1, 140.2, 141.3(C-of dibenzothiophene ring); Anal. Calcd
for C24H18N2O2S2 (430.54): C, 66.95; H, 4.21; N, 6.51 %. Found:
C, 66.80; H, 4.11; N, 6.71%.
[7-(Dibenzothien-2-yl)-3-oxo-5-phenyl-2,3-dihydro-5H-thia-
zolo[3,2-a]pyrimidin-6-yl]acetic acid (5).
A mixture of
compound 2 (4.3 g, 10 mmol), chloroacetic acid (0.95 g, 10
mmol) and anhydrous sodium acetate (2.0 g) was refluxed in a
mixture of glacial acetic acid (30 mL) and acetic anhydride (20
mL) for 4 h. The reaction mixture was cooled and poured onto
crushed ice (50 g). The solid that formed was collected by
filtration and recrystallized from benzene to give 5. Yield, 3.5 g
(75 %); mp 201-3 °C; IR: ꢀ = 3380-3210 (OH), 1690-1685 cm-1
[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo-
[3,2-a]pyrimidin-6-yl]acetic acid (3). 1,2-Dibromoethane (1.9
mL, 10 mmol) in DMF (20 mL) was added dropwise to a stirred
solution containing compound 2 (4.3 g, 10 mmol) and sodium
hydroxide (0.07 g in 10 mL H2O). The reaction mixture was
refluxed for 2 h then stirred at room temperature for an
additional 2 h. The solid product that formed was collected by
filtration, washed with water and triturated with ethanol to give
colorless product which recrystallized from ethanol to give 3.
Yield, 3.4 g (74 %); mp 163-5 °C; IR: ꢀ = 3390-3170 (OH),
1695 cm-1 (CO); 1H NMR (CDCl3): ꢁ = 2.71-2.85 (m, 4H, 2CH2
of thiazole), 3.96 (s, 2H, CH2), 4.71 (s, 1H, methine), 7.51-8.21
(m, 12H, ArH), 10.80 (s, 1H, OH, exchangeable); 13C NMR:
ꢁ=21.6(C-2), 28.1(CH2), 56.2(C-3), 62.7(C-5), 125.1(C-6),
138.2(C-7), 163.4(CO), 176.2(C-8a); Anal. Calcd for
C26H20N2O2S2 (456.58): C, 68.39; H, 4.42; N, 6.14%. Found: C,
68.53; H, 4.51; N, 6.26%.
1
(CO); H NMR (CDCl3); ꢁ = 2.85 (s, 2H, CH2 of thiazole), 3.11
(s, 2H, CH2), 4.12 (s, 1H, methine), 7.15-7.85 (m, 12H, ArH),
10.65 (s, 1H, OH, exchangeable); Anal. Calcd for C26H18N2O3S2
(470.56): C, 66.36; H, 3.86; N, 5.95%. Found: C, 66.50; H, 3.97;
N, 5.81%.
[2-Benzylidene-7-(dibenzothien-2-yl)-3-oxo-5-phenyl-2,3-
dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl]acetic acid (6). A
mixture of compound 5 (4.7, 10 mmol) and benzaldehyde (1.1
mL, 10 mmol) in glacial acetic acid (25 mL) containing
anhydrous sodium acetate (1 g) was refluxed for 6 h. The
reaction mixture left to cool then poured onto crushed ice (30 g)
and the solid that formed was recrystallized from dioxane to
give 6. Yield, 3.8 g (68%); mp 230-2 °C; IR: ꢀ = 3405-3190
(OH), 1690-1680 cm-1 (CO); MS: m/z = 558 (M+); Anal. Calcd
for C33H22N2O3S2 (558.67): C, 70.95; H, 3.97; N, 5.01%. Found:
C, 70.81; H, 3.82; N, 5.15%.
[8-(Dibenzothien-2-yl)-6-phenyl-3,4-dihydro-2H,6H-pyrim-
ido[2,1-b][1,3]thiazin-7-yl]acetic acid (4). 1,3-Dibromopropane
(1 mL, 5 mmol) in DMF (20 mL) was added dropwise to a
stirred solution containing compound 2 (2.2 g, 5 mmol) and
sodium hydroxide (0.07 g in H2O, 10 mL). The reaction mixture
was refluxed for 3 h then stirred at room temperature for an
additional 2 h. The solid product that formed was collected by
filtration, washed with water and triturated with ethanol to give
colorless product, which recrystallized from ethanol to give 4.
Yield 1.6 g (67 %); mp 183-5 °C. IR: ꢀ = 3385-3180 (OH), 1690
[6-(Dibenzothien-2-yl)-3,8-diphenyl-2,3-dihydro-8H-isoxa-
zolo[5',4':4,5]thiazolo[2,3-a]pyrimidin-7-yl]acetic acid (7). A
mixture of compound 6 (2.2 g, 4 mmol) and hydroxylamine
hydrochloride (0.28 g, 4 mmol) was refluxed in pyridine (25
mL) for 6 h. The reaction mixture was cooled then poured onto
ice-HCl (30 g, 10 mL) and the solid that formed was collected
by filtration and recrystallized from dioxane to give 7. Yield,
1.5g (66 %); mp 213-5 °C; IR: ꢀ = 3395-3185 (multiple bands,
1
OH, NH), 1685 cm-1 (CO); H NMR (DMSO-d6): ꢁ = 2.76 (s,
1
cm-1 (CO); H NMR (CDCl3): ꢁ = 2.65-2.93 (m, 6H, 3CH2 of
2H, CH2), 4.11-4.30 (br s, 2H, 2CH, two methine), 7.35-8.12 (m,

Jul-Aug 2008
A Facile Synthesis and Heteroannulation of Thiazolopyrimidine
997
chloride (5.79, 12 mmol) in dry acetone (30 mL) at 0-5 °C then
the mixture was stirred for further 1 h at room temperature. The
reaction mixture was added to crushed ice (40 g) and the
precipitated product was collected by filtration to give the acid
azide 12.Yield, 3.8 g (65%); mp 117-9 °C (with decomposition);
IR: ꢁ = 2215 (CON3), 1680 cm-1 (CO).
17H, ArH), 9.12 (s, 1H, NH, exchangeable), 10.90 (s, 1H, OH,
exchangeable); 13C NMR: ꢀ=28.3(CH2), 59.6(C-4), 62.6(C-9),
78.8(C-8a), 114.2(C-5), 137.3(C-6), 160.1(C-7a), 162.2(C-2a),
165.2(CO); 119.1, 119.9, 120.2, 120.9, 123.2, 125.1(C-of phenyl
ring of oxazole); Anal. Calcd for C33H23N3O3S2 (573.69): C,
69.09; H, 4.04; N, 7.32%. Found: C, 69.22; H, 4.21; N, 7.16%.
[1-(2-Cyanoethyl)-4-(dibenzothien-2-yl)-2-mercapto-6-
phenyl-1,6-dihydropyrimidin-5-yl]acetic acid (8). A mixture
of compound 2 (4.3 g, 10 mmol) and acrylonitrile (0.74 mL, 14
mmol) in pyridine (30 mL) was refluxed for 6 h. The colourless
solid which formed after concentration and cooling was
recrystallized from ethanol to give 8. Yield 3.6 g (74 %); mp
216-8 °C; IR: ꢁ = 3375-3190 (OH), 2510 (SH), 2210 (CN), 1685
cm-1 (CO); 1H NMR (CDCl3): ꢀ = 2.22 (t, 2H, CH2), 2.86 (s, 2H,
CH2), 3.3 (t, 2H, CH2CN), 4.35 (s, 1H, methine), 7.14-7.95
(13H, ArH and SH), 10.76 (s, 1H, OH, exchangeable); MS: m/z
= 483 (M+); Anal. Calcd for C27H21N3O2S2 (483.61): C, 67.06; H,
4.38; N, 8.69%. Found: C, 67.18; H, 4.50; N, 8.73%.
[8-(Dibenzothien-2-yl)-2-oxo-6-phenyl-3,4-dihydro-2H,6H-
pyrimido[2,1-b][1,3]thiazin-7-yl]acetic acid (9). Compound 8
(2 g) in a mixture of glacial acetic acid (30 mL) and
hydrochloric acid (10 mL) was refluxed for 5 h. The reaction
mixture was concentrated by evaporation under reduced
pressure. The solid that formed was collected by filtration,
washed with water and recrsytallized from dioxane to give 9.
Yield 1.4g (69%); mp 195-7°C; IR: ꢁ = 3390-3200 (OH), 1695-
1690 cm-1 (CO);1H NMR (CDCl3): ꢀ = 2.81 (s, 2H, CH2), 2.90-
3.1 (m, 4H, 2CH2 of thiazine), 4.13 (s, 1H, methine), 7.51-8.13
(m, 12H, ArH), 10.76 (s, 1H, OH, exchangeable); MS: m/z =
484 (M+); Anal. Calcd for C27H20N2O3S2 (484.59): C, 66.92; H,
4.16; N, 5.78%. Found: C, 66.79; H, 4.01; N, 5.57%.
General procedure for the preparation of triazole
derivatives (13-16). A cold solution of compound 12 (0.96 g, 2
mmol) in absolute ethanol (25 mL) was added to a cold solution
of active methylene compounds (2 mmol) (viz malononitrile,
ethyl cyanoacetate, ethyl acetoacetate and diethyl malonate) in
ethanolic sodium ethoxide solution (prepared from sodium 1.66
g in absolute ethanol 20 mL). The reaction mixture was stirred at
room temperature overnight then the solvent was evaporated
under vacuum. The concentrated ethanol solution was poured
onto crushed ice (50 g) and the solid obtained was collected by
filtration and recrystallized to give the compounds 13-16.
5-Amino-1-{2-[7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidin-6-yl]acetyl}-1H-1,2,3-triazole-4-
carbonitrile (13). Yield, 0.73g (66%) (benzene); mp 195-7 °C;
IR: ꢁ = 3350, 3280 (NH2), 2220 (CN), 1680 cm-1 (CO); 1H NMR
(CDCl3): ꢀ = 2.71-2.95 (m, 4H, 2CH2 of thiazole), 3.95 (s, 2H,
CH2), 4.51 (s, 1H, methine), 5.85 (br s, 2H, NH2), 7.51-8.25 (m,
12H, ArH); Anal. Calcd for C29H21N7OS2 (547.66): C, 63.60; H,
3.86; N, 17.90%. Found: C, 63.72; H, 3.95; N, 17.79%.
Ethyl 5-amino-1-{2-[7-(dibenzothien-2-yl)-5-phenyl-2,3-
dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl]acetyl}-1H-1,2,3-
triazole-4-carboxylate (14). Yield, 0.74g (62%) (xylene); mp
1
226-8 °C; IR: ꢁ = 3340, 3270 (NH2), 1725, 1680 cm-1 (CO); H
NMR (CDCl3): ꢀ = 1.40 (t, 3H, CH3), 2.65-2.95 (m, 4H, 2CH2 of
thiazole), 3.75 (s, 2H, CH2), 4.12 (q, 2H, CH2), 4.65 (s, 1H,
methine), 5.91 (br s, 2H, NH2), 7.61-8.23 (m, 12H, ArH); Anal.
Calcd for C31H26N6O3S2 (594.71): C, 62.61; H, 4.41; N, 14.13%.
Found: C, 62.49; H, 4.63; N, 14.25%.
[3-Benzylidene-8-(dibenzothien-2-yl)-2-oxo-6-phenyl-3,4-
dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-7-yl]acetic acid
(10). A mixture of compound 9 (4.8 g, 10 mmol) and
benzaldehyde (1.1 mL, 10 mmol) in glacial acetic acid (30 mL)
containing anhydrous sodium acetate (1.5 g) was refluxed for 6
h. The reaction mixture was cooled, poured onto crushed ice (30
g) and the solid formed was recrystallized from ethanol to give
10. Yield 3.8g (66%); mp 230-2°C; IR: ꢁ = 3410-3180 (OH),
1690-1680 cm-1 (CO); 1H NMR (CDCl3): ꢀ = 2.90 (s, 2H, CH2),
3.70 (s, 2H, CH2 of thiazine), 4.20 (s, 1H, methine), 7.13-8.11
(m, 18H, ArH and benzylic proton), 10.50 (s, 1H, OH,
exchangeable); Anal. Calcd for C34H24N2O3S2 (572.70): C,
71.31; H, 4.22; N, 4.89%. Found: C, 71.50; H, 4.32; N, 4.96%.
[8-(Dibenzothien-2-yl)-3,6-diphenyl-2,3-dihydro-4H,6H-
isoxazolo[4,5-e]pyrimido[2,1-b][1,3]thiazin-7-yl]acetic acid
(11). A mixture of compound 10 (2.3 g, 4 mmol) and
hydroxylamine hydrochloride (0.28 g, 4 mmol) in pyridine (30
mL) was refluxed for 6 h. The reaction mixture was cooled, then
poured onto crushed ice (40 g) and the solid product was
collected by filtration and recrystallized from DMF to give 11.
Yield, 1.7 g (69%); mp 207-9 °C; IR: ꢁ = 3390-3180 (multiple
Ethyl 1-{2-[7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-
thiazolo[3,2-a]pyrimidin-6-yl]acetyl}-5-methyl-1H-1,2,3-tria-
zole-4-carboxylate (15). Yield, 0.73 (61%) (xylene); mp 240-2
1
°C; IR: ꢁ = 1725, 1680 cm-1 (CO); H NMR (CDCl3): ꢀ = 1.40
(t, 3H, CH3), 2.50 (s, 3H, CH3), 2.85-2.95 (m, 4H, 2CH2 of
thiazole), 3.50 (s, 2H,CH2), 4.20 (q, 2H, CH2), 4.25 (s, 1H,
methine), 7.23-8.31 (m, 12H, ArH); Anal. Calcd for
C32H27N5O3S2 (593.72): C, 64.74; H, 4.58; N, 11.80 %. Found:
C, 64.85; H, 4.67; N, 11.96%.
Ethyl 1-{2-[7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidin-6-yl]acetyl}-5-oxo-4,5-dihydro-
1H-1,2,3-triazole-4-carboxylate (16). Yield, 0.68g (57%)
(toluene); mp 217-9 °C; IR: ꢁ = 1730 (CO of ester), 1685-1680
1
cm-1 (CO of amide); H NMR (CDCl3): ꢀ = 1.3 (t, 3H, CH3),
2.71-2.90 (m, 4H, 2CH2 of thiazole), 3.62 (s, 2H, CH2), 4.11 (q,
2H, CH2), 4.35, 4.51 (2s, 2H, two methines), 7.15-8.11 (m, 12H,
ArH); Anal. Calcd for C31H25N5O4S2 (595.69): C, 62.51; H, 4.23;
N, 11.76%. Found: C, 62.65; H, 4.34; N, 11.85%.
1
bands, OH, NH), 1690 cm-1 (CO); H NMR (DMSO-d6): ꢀ =
2.91 (s, 2H, CH2), 3.60 (s, 2H, CH2 of thiazine), 4.15-4.30 (br
s, 2H, two methine), 9.55 (br s, 1H, NH, exchangeable); 10.75
(s, 1H, OH, exchangeable); Anal. Calcd for C34H25N3O3S2
(587.71): C, 69.48; H, 4.29; N, 7.15%. Found: C, 69.61; H, 4.40;
N, 7.31%.
[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo-
[3,2-a]pyrimidin-6-yl]acetyl azide (12). A saturated solution of
sodium azide (0.78 g, 12 mmol) in H2O (2 mL) was added
dropwise to a stirred solution of thiazolopyrimidinylacetyl
5-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thia-
zolo[3,2-a]pyrimidin-6-yl]methyl}-3-phenyl-1,3,4-oxadiazol-
2(3H)-one (17). A mixture of compound 12 (0.96 g, 2 mmol)
and phenyl isocyanate (3 mL) in dry benzene (40 mL) was
heated under reflux for 5 h. The solid that separated after
concentration and cooling was recrystallized from benzene to
give 17. Yield, 0.76 g (69%); mp 201-3 °C; IR: ꢁ = 1725 cm-1
(CO); 1H NMR (CDCl3): ꢀ = 2.63-2.85(m, 4H, 2CH2 of
thiazole), 3.42 (s, 2H, CH2), 4.35 (s, 1H, methine), 7.37-8.13(m,

998
A.A. Aly
Vol 45
17H, ArH); Anal. Calcd for C33H24N4O2S2 (572.70): C, 69.21; H,
4.22; N, 9.78%. Found: C, 69.11; H, 4.10; N, 9.86%.
Anal. Calcd for C33H24N4O2S2 (572.70): C, 69.21; H, 4.22; N,
9.78%. Found: C, 69.35; H, 4.37; N, 9.86%.
3-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thia-
zolo[3,2-a]pyrimidin-6-yl]methyl}oxazolidine-2,4(3H,5H)-
dione (18a) and 3-{[7-(dibenzothien-2-yl)-5-phenyl-2,3-
dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl]methyl}thiazol-
idine-2,4(3H,5H)-dione (18b). A solution of 12 (0.96 g, 2
mmol) in dry benzene (30 mL), containing piperidine (1 mL),
glycolic acid and/or thioglycolic acid (3 mmol) was heated
under reflux temperature for 2 h. The solvent was evaporated
under reduced pressure and the residue was redissolved in ether
(40 mL). The solution was washed with 10% sodium carbonate
(3 x 25 mL) and water (40 mL), dried over anhydrous Na2SO4.
Evaporation of the dried etheral layer under vacuum gave the
compounds 18a,b.
18a; Yield, 0.71g (71%) (ethanol); mp 214-6 °C; IR: ꢀ =
1710 cm-1 (CO); 1H NMR (CDCl3): ꢁ = 2.80-2.95 (m, 4H, 2CH2
of thiazole), 3.40, 3.60 (2s, 4H, 2CH2), 4.31 (s, 1H, methine),
7.23-8.13 (m, 12H, ArH); Anal. Calcd for C28H21N3O3S2
(511.62): C, 65.73; H, 4.14; N, 8.21%. Found: C, 65.52; H, 4.10;
N, 8.09%.
REFERENCES
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18b; Yield, 0.84g (76%) (ethanol); mp 230-2 °C; IR: ꢀ =
1705 cm-1 (CO); MS: m/z = 527 (M+); Anal. Calcd for
C28H21N3O2S3 (527.68): C, 63.73; H, 4.01; N, 7.96%. Found: C,
63.84; H, 4.18; N, 7.83%.
2-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thia-
zolo[3,2-a]pyrimidin-6-yl]methyl}oxazol-5(4H)-one (19). A
mixture of 12 (0.96 g, 2 mmol) and glycine (0.15 g, 2 mmol)
in dry toluene (30 mL) containing piperidine (1 mL) was
heated under reflux for 7 h. The solid that separated after
concentration and cooling was recrystallized from toluene to
give 19. Yield, 0.73g (73%); mp 223-5 °C; IR: ꢀ = 1726
1
(CO), 1610 cm-1 (C=N); H NMR (CDCl3): ꢁ = 2.70-2.81 (m,
4H, 2CH2 of thiazole), 3.71, 3.92 (2s, 4H, 2CH2), 4.57 (s, 1H,
methine), 7.63-8.25 (m, 12H, ArH); Anal. Calcd for
C28H21N3O2S2 (495.62): C, 67.85; H, 4.27; N, 8.48%. Found:
C, 67.76; H, 4.10; N, 8.31%.
[10] Kihara, N. ; Tomino, I.; Takei, M. Jpn Patent 61 /76488 A2
[76488], 1986; Chem. Abstr. 1986, 105, 208915 w.
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1-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thia-
zolo[3,2-a]pyrimidin-6-yl]methyl}-3-o-tolylurea (20).
A
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Hawary, N.A. Egypt J. Chem. 1993, 36, 176. (b) Arief, M.M.H.
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[19] Mamolo, M.G.; Zampieri, D.; Vio, L.; Fermeglia, M.; Ferrone, M.;
Pricl, S.; Scialino, G.; Banfi, E. Bioorg. & Med. Chem. 2005, 13, 3797.
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[21] Smalley, R.K.; Teguiche, M. Synthesis 1990, 654.
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D.; Epton, H.A.; Harbour. A. J. Appl. Bacteriol. 1995, 78, 97.
mixture of compound 12 (0.96 g, 2 mmol) and anthranilic acid
(0.27 g, 2 mmol) in dry benzene (30 mL) was refluxed for 30 min,
the reaction mixture was allowed to cool and the solid which
precipitated after cooling, was collected by filtration, dried and
recrystallized from benzene to give 20.Yield, 1.0 g (84%); mp
242-4 °C; IR: ꢀ = 3460-3260 (OH, NH), 1690-1680 cm-1 (CO);
MS: m/z = 590 (M+); Anal. Calcd for C33H26N4O3S2 (590.72): C,
67.10; H, 4.44; N, 9.48%. Found: C, 67.23; H, 4.53; N, 9.61%.
3-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thia-
zolo[3,2-a]pyrimidin-6-yl]methyl}quinazoline-2,4(1H,3H)-
dione (21). A solution of 20 (1 g) in acetic anhydride (10 mL)
was refluxed for 1 h. The reaction mixture was cooled, poured
onto crushed ice (50 g) and the precipitated product was
collected by filtration and recrystallized from n-butanol to give
21. Yield, 0.61 g (63%); mp 196-8 °C; IR:ꢀ = 3210 (NH), 1680-
1
1670 cm-1 (CO); H NMR (DMSO-d6): ꢁ = 2.72-2.93 (m, 4H,
2CH2 of thiazole), 3.95 (s, 2H, CH2), 4.45 (s, 1H, methine),
7.61-8.13 (m, 16H, ArH), 9.22 (br s, 1H, NH, exchangeable);