Synthesis and pharmacological activity of annelated pyrimidine derivatives

Article abstract of DOI:10.1080/10426500500326792

A series of 2,3-diglycosylpyrimidine 4, annelated pyrimidine derivatives, pyrazolo-[3,4-d]pyrimidine 8, ditetrazolo[1,5-a;1′,5′-c]pyrimidine 9, 2,9a,10-triazaanthracene 12, thieno- [2,3-d]pyrimidine 14, 9-thia-1,3,5,7-tetraazafluorene-8-one 15, 7-oxa-9-th

Full text of DOI:10.1080/10426500500326792

Phosphorus, Sulfur, and Silicon, 181:1285–1298, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500326792
Synthesis and Pharmacological Activity of Annelated
Pyrimidine Derivatives
A. A. Aly
Chemistry Department, Benha University, Benha, Egypt
A
series of 2,3-diglycosylpyrimidine 4, annelated pyrimidine derivatives,
pyrazolo-[3,4-d]pyrimidine 8, ditetrazolo[1,5-a;1ꢀ,5ꢀ-c]pyrimidine 9, 2,9a,10-
triazaanthracene 12, thieno- [2,3-d]pyrimidine 14, 9-thia-1,3,5,7-tetraazafluorene-
8-one 15, 7-oxa-9-thia-1,3,5-triazafluorene-8-one 16, and 5-oxa-9-thia-1,3-
diazafluorene 21a,b derivatives have been synthesized via
a sequence of
heterocyclization reactions of suitably functionalized 6-[5-(4-bromophenyl)oxazol-
4-yl]-1,2,3,4-tetrahydro-2-thioxo-4-oxopyrimidine-5-carbonitrile (2) with different
electrophiles and nucleophiles. The new compounds were prepared with the
objective to study their pharmacological properties.
Keywords 2-Methylsulfanylpyrimidine; azafluorenone; pharmacological properties;
thienopyrimidine
INTRODUCTION
Pyrimidines and fused pyrimidines, being an integral part of DNA
and RNA, play an essential role in several biological processes and
have considerable chemical and pharmacological importance. Particu-
larly, the pyrimidine ring can be found in the nucleoside antibiotics,
antibacterial, antitumor, cardiovascular, as well as agrochemical and
veterinary products.1−9 In view of these observations and in continua-
tion of our interest in developing efficient syntheses of polyfunctionally
substituted heterocycles utilizing the readily obtainable pyrimidine as
starting material,10−12 it is worthwhile to explore their potential utility
for the synthesis of polyfunctionally substituted pyrimidine derivatives
useful for the optimization of biological activity.
Received April 20, 2004; accepted May 21, 2005.
All strains were kindly supplied from the Botany Department, Faculty of Science,
Benha University, Benha, Egypt.
Address correspondence to A. A. Aly, Benha University, Department of Chemistry,
Faculty of Science, Benha, Egypt. E-mail: alymaboud@hotmail.com
1285

1286
A. A. Aly
RESULTS AND DISCUSSION
In the present work, 6-[5-(4-bromophenyl)oxazol-4-yl]-1,2,3,4-
tetrahydro-2-thioxo-4-oxopyrimidine-5-carbonitrile (2), used as
a
starting material, was conveniently prepared from the reaction of 5-
(4-bromophenyl)oxazole-4-carbaldehyde (1)13 with ethyl cyanoacetate
and thiourea.14,15 The reaction of 2 with 2, 3, 4, and 6-tetra-O-acetyl-α-
D-glucopyranosyl bromide (3)16 in the presence of aqueous potassium
hydroxide gave 6-[5-(4-bromophenyl)oxazol-4-yl]-4-oxo-2-(2,3,4,6-tetra-
O-acetyl-β-D-glucopyranosylsulfanyl)-3-(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranos-yl)-3,4-dihydropyrimidine-5-carbonitrile (4). The struc-
ture of compound 4 was confirmed on the basis of the elemental
analysis and spectral data. The IR spectrum showed the absence of an
NH group and the presence of an absorption band at 1685 cm−1 due to
the carbonyl of pyrimidinone in addition to the acetoxy carbonyl groups
at 1765–1750 cm−1. Also, the 1H NMR spectrum showed the presence of
8 OAc groups and a doublet at δ5.60 with a spin-spin coupling constant
10.55 Hz, which corresponds to the diaxial orientation of the H-1ꢀ and
H-2ꢀ protons, indicating the presence of only the β-configuration.17
We then investigated 2 in syntheses of S-alkylsulfanylpyrimidine
derivatives, which have been recently identified as highly specific
reverse transcriptase inhibitors of HIV.18 Thus, the reaction of 2
with methyl iodide in the presence of ethanolic sodium ethox-
ide solution afforded 4-[5-(4-bromophenyl)oxazol-4-yl]-6-hydroxy-2-
methylsulfanylpyrimidine-5-carbonitrile (5) with a good yield.
The electron-deficient nature of the pyrimidine ring and the high
reactivity of a methylthio group towards nucleophilic reagents facil-
itate the synthesis of a large number of condensed pyrimidines via
nucleophilic aromatic substitution.19,20 Thus, the reaction of 5 with
POCl3/PCl5 on a water bath yields 4-[5-(4-bromophenyl)oxazol-4-yl]-6-
chloro-2-methylsulfanylpyrimidine-5-carbonitrile (6). The treatment of
6 with hydrazine hydrate in refluxing 1-butanol for 2 h afforded 4-[5-(4-
bromophenyl) oxazol-4-yl]-2,6-dihydrazino-pyrimidine-5-carbonitrile
(7), which was further cyclized to pyrazolopyrimidine 8 by refluxing in
1-butanol for 5 h. The formation of 8 occurs via a nucleophilic attack
of the hydrazino moiety to the cyano group in the ortho position,
leading to a fused pyrimidine 8. The IR spectrum of 8 displays a
lack of absorption of the cyano group and the presence of different
bands in the region between 3340–3195 cm−1 (NH2 and NHNH2).
Moreover, the presence of latter groups was confirmed by the 1H NMR
spectrum, which consists of a series of D2O exchangeable signals that
present different chemical shifts. Also, when an acidic solution of 7 was

Annelated Pyrimidine Derivatives
1287
allowed to react with an aqueous solution of sodium nitrite at 0–5◦C,
ditetrazolo-[1,5-a;1ꢀ,5ꢀ-c]-pyrimidine 9 was obtained (Scheme 1).
SCHEME 1
The treatment of 6 with thiourea21 in an ethanolic solution
produced 4-[5-(4-(bromophenyl)oxazol-4-yl]-6-mercapto-2-methylsulf-
anylpyrimidine-5-carbonitrile (10). The treatment of 10 with an-
thranilic acid in 1-butanol afforded pyrimidine derivative 11, which
cyclized to 3-[5-(4-bromophenyl)oxazol-4-yl]-1-methylsulfanyl-9-oxo-
9H-2,9a,10-triazaanthracene-4-carbonitrile (12) by heating in acetic
anhydride. Also, the alkylation of 10 with ethyl chloroacetate in
an ethanolic solution containing sodium acetate afforded S-alkylated
derivative 13, which cyclized to thienopyrimidine derivative 14 in

1288
A. A. Aly
ethanol containing sodium ethoxide. Of particular interest was a cy-
clocondensation reaction of thienopyrimidine 14 with phenyl isothio-
cyanate or by heating in acetic anhydride resulted in the formation of
tricyclic heterocycles 15 and 16, respectively (Scheme 2).
SCHEME 2
The saponification of the o-aminoester 14 resulted in the formation
of the corresponding carboxylic acid 17, which, upon treatment with
orthophosphoric acid at r.t., underwent decarboxylation to give amino
compound 18.22 On the other hand, when treating 17 with orthophos-
phoric acid at 100◦C, the product was identified as thienopyrimidine

Annelated Pyrimidine Derivatives
1289
19, which was also prepared via treatment of 18 with orthophosphoric
acid at 100◦C. The condensation of 19 with aromatic aldehydes (viz ben-
zaldehyde and p-anisaldehyde) in refluxing ethanol containing catalytic
amounts of piperidine furnished the chalcones 20a,b, while the reac-
tion of 19 with arylmethylene malononitrile provided 2-amino-8-[5-(4-
bromophenyl)oxazol-4-yl]-6-methylsulfanyl-4-(phenyl-/4-methoxyphe-
nyl)-4H-1-oxa-9-thia-5,7-diazafluorene-3-carbonitrile (21a,b) (Scheme
3). Structures of synthesized compounds were assigned on the basis of
elemental analysis and spectral data (cf. Experimental Section).
SCHEME 3
ANTIMICROBIAL ACTIVITY
Antimicrobial activities of some synthesized compounds were deter-
mined in vitro using hole plate and filter paper disc methods.23
A

1290
A. A. Aly
variety of species of Gram positive and Gram negative bacteria in addi-
tion to some fungal plant pathogens were used. Also, a comparison be-
tween the activity of our synthesized compounds and sulphadiazine as
a standard drug was discussed. The tested compounds were dissolved in
10% acetone (v/v); different concentrations have been chosen (125, 250,
500 µg/mL). A qualitative screening was performed on all compounds,
while quantitative assays were done only on active compounds. The
results are summarized in Table I.
The data indicated that compounds 4, 5, 10, 15, 16, and 21b were
highly active towards selected pathogens. The high activity of these
compounds resulted from the presence of a nucleoside moiety at-
tached|to nitrogen or sulphur atoms, the presence of toxopheric system
|
|
(
O), and the presence of polynuclear mixed heterocyclic
C
C
C
systems; the oxazine and pyran moiety augmented the reactivity to-
wards the tested microorganisms.
Compounds 1, 2, 9, 12, 14, 18, and 20a are only moderately active
towards different strains of bacteria and fungi as compared with the
standard due to the presence of a polynuclear nonmixed heterocyclic
system.
TABLE I The Antimicrobial Activity of Tested Compounds
Bacillus
Subtilis
Bacillus
Cereus
Escherichia
Coli
Aspergillus
niger
Compound
no.
A
MIC
A
MIC
A
MIC
A
MIC
1
2
4
5
9
10
12
14
15
16
18
20a
+
++
250
500
500
250
500
250
250
250
500
250
125
125
250
500
+
++
+
500
125
250
250
250
250
125
125
250
125
250
250
250
250
+
+
125
250
125
500
250
125
125
250
125
250
125
500
250
125
−
−
−
−
+ + +
++
++
++
+
++
+
500
250
500
125
250
250
250
500
250
250
500
125
+ + +
+
+
+
+ + +
+
++
+
++
+
++
+
++
+
+
+
+ + +
+ + +
++
++
+ + +
+
++
++
+
+
+
+
++
+
++
+ + +
+
+
21b
++
++
++
+
Sulphadiazine
++
+
A = antimicrobial activity of tested compounds.
MIC = minimum inhibitory concentration.
+ > 5 mm slightly active.
++ > 7 mm moderately active.
+ + + > 9 mm highly active.

Annelated Pyrimidine Derivatives
1291
In summary, we have demonstrated the ability of the pyrimidine
derivative 2 to undergo annelation reactions under rather mild con-
ditions, providing an efficient synthetic method for the preparation of
various pyrimidine derivatives, which enhanced antibacterial and an-
tifungal activity.
EXPERIMENTAL
Melting points are uncorrected. IR spectra in KBr were recorded on a
1
Perkin Elmer 298 spectrophotometer. H NMR spectra were obtained
on a Varian Gemini 200 MHz instrument using TMS as an internal
reference (Chemical shifts are expressed as δ, ppm.) Mass spectra were
recorded on Shimadzu GCMS-QP 1000 EX instrument (70 ev EI mode).
All reactions were monitored by thin layer chromatography and carried
out on 0.2 mm silica gel 60 F254 (Merck) plates.
6-[5-(4-Bromophenyl)oxazol-4-yl]-1,2,3,4-tetrahydro-2-
thioxo-4-oxopyrimidine-5-carbonitrile (2)
A mixture of 5-(4-bromophenyl)oxazole-4-carbaldehyde (1)13 (0.01 mol),
ethyl cyanoacetate (0.01 mol), thiourea (0.01 mol), and potassium car-
bonate (0.01 mol) in absolute ethanol (40 mL) was refluxed for 24 h.
The precipitate, which formed after cooling and acidification, was fil-
tered off and crystallized from a DMF-water mixture to give 2.14,15
Yield, 52%, m.p. 236–238◦C, IR: ν = 3200–3190 (NH), 2221 (C N), 1679
1
(CO), 1610 (C N), 1265 cm−1 (CS); H NMR (DMSO): δ = 7.10–8.02
(m, 5H, ArH and oxazole H-2) and 11.7 (br s, 2H, 2NH exchange-
able); MS: m/z (%) 375 (M+, 86.4), 376 (M+ + 1, 1.08); anal. calcd. for
C14H7BrN4O2S: C,44.82; H, 1.88; N, 14.93%. Found: C, 44.70; H, 1.73; N,
14.81%.
6-[5-(4-Bromophenyl)oxazol-4-yl]-4-oxo-2-(2,3,4,6-tetra-O-
acetyl-β-D-gluco-pyranosylsulfanyl)-3-(2,3,4,6-tetra-O-acetyl-
β-D-glucopyranosyl)-3,4-dihydro-pyrimidine-5-carbonitrile (4)
To a solution of 2 (0.001 mol) and KOH (0.002 mol) in distilled water
(10 mL) a solution of 3 (0.0021 mol) in acetone (40 mL) was added. The
reaction mixture was stirred for 4 h at r.t. until the starting material
was consumed (TLC). The mixture was evaporated under reduced pres-
sure, and the residue was washed with distilled water to remove the
potassium bromide that formed. The solid product was dried and crys-
tallized from ethanol to give 4. Yield, 58%, m.p. 182–184◦C, IR: ν = 2226
(C N), 1765–1750 (COCH3), 1685 (CO), 1618 (C N), 1559 cm−1 (C C);

1292
A. A. Aly
1H NMR (DMSO): δ = 1.77, 1.98, 2.06, 2.11, 2.15, 2.19, 2.21, 2.30 (8s,
24H, 8 CH3CO), 3.70–4.28 (m, 6H, H-5ꢀ, H-5ꢀꢀ, 2 × H-6ꢀ, 2× H-6ꢀꢀ), 4.89–
5.32 (m, 2H, H-4ꢀ, H-4ꢀꢀ), 5.40–5.48 (m, 4H, H-3ꢀ, H-3ꢀꢀ, H-2ꢀꢀ, H-1ꢀꢀ), 5.59
(t, 1H, J = 9.1 Hz, H-2ꢀ), 5.60 (d, 1H, J = 10.55 Hz, H-1ꢀ), 7.11–7.98 (m,
5H, ArH and oxazole H-2); anal. calcd. for C42H43BrN4O20S: C, 48.70;
H, 4.18; N, 5.41%. Found: C, 48.83; H, 4.30; N, 5.30%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-hydroxy-2-
methylsulfanylpyrimidine-5-carbonitrile (5)
A solution of 2 (0.01 mol) and methyl iodide (0.01 mol) in ethanolic
sodium ethoxide (prepared by dissolving 1.0 g of sodium metal in 50 mL
of ethanol) was heated under reflux for 5 h. The reaction mixture was
then cooled and poured onto ice-cold water. The solid product obtained
after acidification with hydrochloric acid was filtered off, washed with
water, and crystallized from ethanol to give 5. Yield, 85%, m.p. 201–
203◦C, IR: ν = 3480 (OH), 2218 (C N), 1615 (C N), 1601 cm−1 (C C);
1H NMR (CDCl3): δ = 2.53 (s, 3H, CH3), 7.1–8.10 (m, 5H, ArH and
oxazole H-2) and 10.61 (s, 1H, OH, exchangeable); MS: m/z (%) 389 (M+,
71.2), 390 (M+ + 1, 2.01); anal. calcd. for C15H9BrN4O2S: C, 46.29; H,
2.33; N, 14.39%. Found: C, 46.40; H, 2.46; N, 14.51%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-chloro-2-
methylsulfanylpyrimidine-5-carbonitrile (6)
A mixture of 5 (0.0095 mol), POCl3 (0.29 mol), and PCl5 (0.015 mol)
was refluxed on a water bath for 4 h. The reaction mixture was poured
gradually on crushed ice, and the solid that separated was filtered off
and crystallized from benzene to give 6. Yield, 70%, m.p. 195–197◦C,
1
IR: ν = 2223 (C N), 1620 (C N), 1603 cm−1 (C C); H NMR (CDCl3):
δ = 2.56 (s, 3H, CH3), 7.13–8.12 (m, 5H, ArH and oxazole H-2); anal.
calcd. for C15H8BrClN4OS: C, 44.19; H, 1.98; N, 13.74%. Found: C, 44.30;
H, 1.85; N, 13.86%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-2,6-dihydrazinopyrimidine-
5-carbonitrile (7)
A mixture of chloropyrimidine 6 (0.06 mol) and hydrazine hydrate
(2.3 mL) in 1-butanol was refluxed for 2 h. The resulting solid was
collected by filtration and crystallized from 1-butanol to give 7. Yield,
78%, m.p. 211–213◦C, IR: ν = 3330–3180 (NHNH2), 2219 (C N), 1625
1
(C N), 1601 cm−1 (C C); H NMR (CDCl3): δ = 5.91, 5.96 (br s, 4H,
2NH2), 7.03–8.11 (m, 5H, ArH and oxazole H-2) and 9.11, 9.13 (2br s,

Annelated Pyrimidine Derivatives
1293
2H, 2NH, exchangeable); anal. calcd. for C14H11BrN8O: C, 43.43; H,
2.86; N, 28.94%. Found: C, 43.55; H, 2.74; N, 28.82%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-hydrazino-1H-
pyrazolo[3,4-d]pyrimidin-3-ylamine (8)
A solution of dihydrazinopyrimidine 7 (0.0014 mol) in 1-butanol (20 mL)
was refluxed for 5 h. The solvent was removed at reduced pressure
and the residue crystallized from 1-butanol to give 8. Yield, 88%,
m.p. 283–285◦C, IR: ν = 3340–319 (NH2 and NHNH2), 1612 (C N),
1605 cm−1 (C C); 1H NMR (DMSO): δ = 5.68 (br s, 2H, NH2, exchange-
able), 6.38 (br s, 2H, NH2, exchangeable), 6.99–8.12 (m, 5H, ArH and
oxazole H-2) and 9.12, 9.35 (2s, 2H, 2NH, exchangeable); anal. calcd. for
C14H11BrN8O: C, 43.43; H, 2.86; N, 28.94%. Found: C, 43.55; H, 2.74;
N, 28.83%.
5-[5-(4-Bromophenyl)oxazol-4-yl]ditetrazolo[1,5-A;1ꢀ,5ꢀ-
c]pyrimidine-6-carbonitrile (9)
A solution of sodium nitrite (0.0021 mol) in water (10 mL) was added
to ice and a stirred solution of compound 7 (0.001 mol) in 20% aqueous
hydrochloric acid (10 mL). The mixture was allowed to react for 2 h at
the same temperature. Then the formed precipitate was collected by
filtration and crystallized from methanol to furnish 9. Yield, 69%, m.p.
176–178◦C, IR: ν = 2218 (C N), 1614 (C N), 1095–1055 cm−1 (tetra-
1
zole ring); H NMR (DMSO): δ = 6.99–8.13 (m, 5H, ArH and oxazole
H-2); anal. calcd. for C14H5BrN10O: C, 41.10; H, 1.23; N, 34.23%. Found:
C, 41.21; H, 1.34; N, 34.12%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-mercapto-2-
methylsulfanylpyrimidine-5-carbonitrile (10)
To a solution of chloropyrimidine 6 (0.0012 mol) in ethanol (25 mL),
thiourea (0.0012 mol) was added, and the reaction mixture was heated
under reflux for 10 h. The solid obtained after cooling was crystal-
lized from ethanol to give 10. Yield, 81%, m.p. 190–192◦C, IR: ν = 2370
(SH), 2216 (C N), 1618 (C N), 1601 (C C), 1272 cm−1 (CS); 1H NMR
(CDCl3): δ = 2.58 (s, 3H, SCH3), 3.43 (s, 1H, SH), 6.99–7.89 (m, 5H, ArH
and oxazole H-2); MS: m/z (%) 405 (M+, 70.1), 406 (M+ + 1, 1.98); anal.
calcd. for C15H9BrN4OS2: C, 44.45; H, 2.24; N, 13.82%. Found: C, 44.56;
H, 2.35; N, 13.17%.

1294
A. A. Aly
2-{6-[5-(4-Bromophenyl)oxazol-4-yl)]-5-cyano-2-
methylsulfanylpyrimidin-4-ylamino}benzoic Acid (11)
A mixture of 10 (0.011 mol) and anthranilic acid (0.011 mol) in 1-butanol
(20 mL) was heated under reflux for 8 h. The reaction mixture was
then cooled, and the solid obtained was filtered off and crystallized
from 1-butanol to yield 11. Yield, 73%, m.p. 231–233◦C, IR: ν = 3470–
3205 (OH and NH), 2215 (C N), 1705 (CO), 1614 (C N), 1598 cm−1
1
(C C); H NMR (CDCl3): δ = 2.59 (s, 3H, SCH3), 6.86–7.95 (m, 9H,
ArH and oxazole H-2), 9.35 (s, 1H, NH, exchangeable), 10.31 (s, 1H,
OH, exchangeable); MS: m/z (%) 508 (M+, 32.5), 509 (M+ + 1, 2.6); anal.
calcd. for C22H14BrN5O3S: C, 51.98; H, 2.78; N, 13.78%. Found: C, 51.87;
H, 2.65; N, 13.89%.
3-[5-(4-Bromophenyl)oxazol-4-yl]-1-methylsulfanyl-9-oxo-9H-
2,9a,10-triaza-anthracene-4-carbonitrile (12)
A mixture of 11 (0.002 mol) and acetic anhydride (20 mL) was refluxed
for 4 h. The solid separated on cooling was filtered and crystallized from
DMF to give 12. Yield, 67%, m.p. 201–203◦C, IR: ν = 2223 (C N), 1680
(CO), 1615 cm−1 (C N); 1H NMR (DMSO): δ = 2.53 (s, 3H, CH3), 7.02–
7.99 (m, 9H, ArH and oxazole H-2); anal. calcd. for C22H12BrN5O2S: C,
53.89; H, 2.47; N, 14.28%. Found: C, 53.58; H, 2.58; N, 14.38%.
Ethyl{6-[5-(4-Bromophenyl)oxazol-4-yl]-5-cyano-2-
methylsulfanylpyrimidin-4-yl]-sulfanyl}acetate (13)
A mixture of 10 (0.0019 mol), sodium acetate (0.0035 mol), and ethyl
chloroacetate (0.0019 mol) in ethanol (40 mL) was heated under re-
flux for 3 h. The precipitate that formed on cooling was filtered and
crystallized from benzene to yield 13. Yield, 68%, m.p. 211–213◦C, IR:
ν = 2218 (C N), 1725 (CO), 1617 cm−1 (C N); 1H NMR (CDCl3): δ = 1.2
(t, J = 7.41 Hz, 3H, CH3CH2), 2.59 (s, 3H, SCH3), 3.62 (s, 2H, SCH2),
3.98 (q, J = 7.41 Hz, 2H, CH2CH3), 7.01–8.01 (m, 5H, ArH and oxazole
H-2); anal. calcd. for C19H15BrN4O3S2: C, 46.44; H, 3.08; N, 11.40%.
Found: C, 46.31; H, 3.19; N, 11.53%.
Ethyl 5-Amino-4-[5-(4-bromophenyl)oxazol-4-yl]-2-
methylsulfanylthieno[2,3-d]-pyrimidine-6-carboxylate (14)
To a solution of 13 (0.002 mol) in absolute ethanol (20 mL), sodium
ethoxide solution (50 mg sodium in 25 mL of absolute ethanol) was
added dropwise, and the reaction mixture was heated under reflux for
30 min. The solid that formed while hot was collected and crystallized

Annelated Pyrimidine Derivatives
1295
from ethanol to furnish 14. Yield, 83%, m.p. 187–189◦C, IR: ν = 3320,
1
3300 (NH2), 1730 (CO), 1620 cm−1 (C N); H NMR (CDCl3): δ = 1.3
(t, J = 7.2 Hz, 3H, CH3CH2), 2.56 (s, 3H, SCH3), 4.11 (q, J = 7.2 Hz,
CH2CH3), 5.81 (br s, 2H, NH2), 6.96–7.98 (m, 5H, ArH and oxazole H-2);
anal. calcd. for C19H15BrN4O3S2: C, 46.44; H, 3.08; N, 11.40%. Found:
C, 46.55; H, 3.19; N, 11.51%.
8-[5-(4-Bromophenyl)oxazol-4-yl]-6-methylsulfanyl-3-phenyl-
2-thioxo-2,3-dihydro-1H-9-thia-1,3,5,7-tetraazafluorene-4-
one (15)
To a solution of 14 (0.0011 mol) in pyridine (25 mL) phenyl isothio-
cyanate (0.001 mol) was added, and the reaction mixture was refluxed
in an oil bath for 20 h. The reaction mixture after cooling was poured
into ice/HCl, and the solid that separated was filtered, washed with cold
aqueous ethanol, dried, and crystallized from ethanol-DMF (2:1) to give
15. Yield, 59%, m.p. 214–216◦C, IR: ν = 3280 (NH), 1680 (CO), 1621
(C N), 1260 cm−1 (CS); 1H NMR (CDCl3): δ = 2.58 (s, 3H, CH3), 6.97–
8.01 (m, 10H, ArH and oxazole H-2) and 9.01 (s, 1H, NH, exchangeable);
anal. calcd. for C24H14BrN5O2S3: C, 49.66; H, 2.43; N, 12.06%. Found:
C, 49.79; H, 2.55; N, 12.17%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-methyl-2-methylsulfanyl-
7-oxa-9-thia-1,3,5-triazafluorene-8-one (16)
A sodium salt of the acid derivative 14 (0.0011 mol) (which resulted
from boiling 14 in ethanolic sodium hydroxide solution for 2 h) in acetic
anhydride (20 mL) was heated under reflux for 3 h, concentrated, and
allowed to cool. The solid product was collected, washed with water,
and crystallized from xylene to yield 16. Yield, 61%, m.p. 226–228◦C,
1
IR: ν = 1695 (CO), 1625 (C N), 1602 cm−1 (C C); H NMR (CDCl3):
δ = 2.01(s, 3H, CH3), 2.56 (s, 3H, SCH3), 6.99–8.11 (m, 5H, ArH and
oxazole H-2); anal. calcd. for C19H11BrN4O3S2: C, 46.83; H, 2.28; N,
11.50%. Found: C, 46.94; H, 2.39; N, 11.61%.
5-Amino-4-[5-(4-bromophenyl)oxazol-4-yl]-2-
methylsulfanylthieno[2,3-d]pyrimidine-6-carboxylic Acid (17)
A suspension of 14 (0.001 mol) in ethanolic sodium hydroxide solution
of 10% (50 mL) was heated under reflux for 4 h. The alkaline solu-
tion was acidified with diluted acetic acid and extracted with ether.
The solid separated after evaporation of the dried ethereal layer was

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A. A. Aly
crystallized from ethanol to furnish 17. Yield, 79%, m.p. 241–243◦C,
IR: ν = 3475 −3 160 (OH and NH2), 1707 (CO), 1615 (C N), 1602 cm−1
1
(C C); H NMR (DMSO): δ = 2.54 (s, 3H, CH3), 5.75 (br s, 2H, NH2),
6.96–7.89 (m, 5H, ArH and oxazole H-2) and 10.95 (br s, 1H, OH, ex-
changeable); anal. calcd. for C17H11BrN4O3S2: C, 44.07; H, 2.39; N,
12.09%. Found: C, 44.18; H, 2.50; N, 12.20%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-2-methylsulfanylthieno[2,3-
d]pyrimidin-5-ylamine (18)
A solution of 17 (0.0012 mol) in orthophosphoric acid 85% (30 mL)
was stirred for 20 min at r.t. (until the evolution of CO2 gas ceased).
The reaction mixture was poured on 80 mL of ice-water and then
neutralized with 8% aqueous sodium carbonate. The solid product
formed was filtered and crystallized from 1-butanol to afford 18.
Yield, 72%, m.p. 216–218◦C, IR: ν = 3360–3330 (broad NH2), 1621
(C N), 1604 cm−1 (C C); 1H NMR (CDCl3): δ = 2.55 (s, 3H, CH3),
5.51 (br s, 2H, NH2, exchangeable) 6.01 (s, 1H, thiophene ring), 7.01–
8.11 (m, 5H, ArH and oxazole H-2); anal. calcd. for C16H11BrN4OS2:
C, 45.83; H, 2.64; N, 13.36%. Found: C, 45.72; H, 2.75; N,
13.47%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-2-methylsulfanylthieno[2,3-
d]pyrimidin-5-one (19)
Method A
A solution of 17 (0.0011 mol) in orthophosphoric acid of 85% (30 mL)
was heated under reflux at 100◦C for 8 h. The reaction mixture was
poured on ice water (50 mL), whereupon the solid formed. It was col-
lected by filtration and crystallized from toluene to give 19, yield 70%.
Method B
A solution of 18 (0.0011 mol) in orthophosphoric of 85% acid (30 mL)
was heated under reflux at 100◦C for 7 h. The reaction mixture was
poured on ice water (50 mL), and the solid that separated was filtered
and crystallized to yield a product identified to be 19 by m.p. and m.m.p.
determination. Yield, 73%, m.p. 207–209◦C, IR: ν = 1698 (CO), 1622
(C N), 1605 cm−1 (C C); 1H NMR (CDCl3): δ = 2.56 (s, 3H, CH3), 3.71
(s, 2H, CH2), 7.13–8.12 (m, 5H, ArH and oxazole H-2); MS: m/z (%)
420 (M+, 25.1), 421 (M+ + 1, 1.65); anal. calcd. for C16H10BrN3O2S2: C,
45.72; H, 2.40; N, 10.00%. Found: C, 45.61; H, 2.52; N, 10.12%.

Annelated Pyrimidine Derivatives
1297
General Procedure for the Synthesis of
6-Arylidene-4-[5-(4-bromophenyl)oxazol-4-yl]-2-
methylsulfanylthieno[2,3-d]pyrimidin-5-ones (20a,b)
A mixture of 19 (0.002 mol) and aromatic aldehydes (0.0013 mol),
namely, benzaldehyde or p-anisaldehyde in ethanol (25 mL) contain-
ing a few drops of piperidine was refluxed for 2 h. The precipitate that
separated while hot was collected by filtration and crystallized from
dioxane to furnish 20a,b.
6-Benzylidene-4-[5-(4-bromophenyl)oxazol-4-yl]-2-
methylsulfanylthieno[2,3-d]-pyrimidin-5-one (20a)
Yield, 89%, m.p. 261–213◦C, IR: ν = 1675 (CO), 1625–1620 cm−1 (C N);
1H NMR (CDCl3): δ = 2.54 (s, 3H, CH3), 6.98–7.95 (m, 10H, ArH and
oxazole H-2), 7.85 (s, 1H, CH C); anal. calcd. for C23H14BrN3O2S2: C,
54.34; H, 2.78; N, 8.26%. Found: C, 54.22; H, 2.89; N, 8.38%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-(4-methoxybenzylidene)-
2-methylsulfanylthieno-[2,3-d]pyrimidin-5-one (20b)
Yield, 83%, m.p. 283–284◦C, IR: ν = 1680 (CO), 1624–1620 cm−1 (C N);
1H NMR (CDCl3): δ = 2.53 (s, 3H, SCH3), 3.81 (s, 3H, OCH3), 6.91–7.31
(m, 9H, ArH and oxazole H-2) and 7.81 (s, 1H, CH C); anal. calcd. for
C24H16BrN3O3S2: C, 53.54; H, 3.00; N, 7.80%. Found: C, 53.63; H, 3.11;
N, 7.69%.
General Procedure for the Synthesis of 2-Amino-8-[5-
bromophenyl)oxazol-4-yl]-6-methylsulfanyl-4-(phenyl- or
4-Methoxyphenyl)-4H-1-oxa-9-thia-5,7-diazafluorene-3-
carbonitrile (21a,b)
A mixture of 19 (0.0012 mol) and arylmethylene malononitrile
(0.0012 mol) in ethanol (25 mL) containing a few drops of piperidine
was heated under reflux for 3 h, and the precipitate that formed while
hot was collected by filtration and crystallized from dioxane to afford
21a,b.
2-Amino-8-[5-(4-bromophenyl)oxazol-4-yl]-6-methylsulfanyl-4-
phenyl-4H-1-oxa-9-thia-5,7-diazafluorene-3-carbonitrile (21a)
Yield, 81%, m.p. 273–275◦C, IR: ν = 3350–3330 (broad NH2), 2230
(C N), 1620 cm−1 (C N); 1H NMR (DMSO): δ = 2.53 (s, 3H, CH3), 5.10
(s, 1H, pyran-CH), 5.89 (br s, 2H, NH2), 6.85–7.48 (m, 10H, ArH and

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A. A. Aly
oxazole H-2); anal. calcd. for C26H16BrN5O2S2: C, 54.36; H, 2.81; N,
12.19%. Found: C, 54.48; H, 2.70; N, 12.30%.
2-Amino-8-[5-(4-bromophenyl)oxazol-4-yl]-6-methylsulfanyl-4-
(4-methoxyphenyl)-4H-1-oxa-9-thia-5,7-diazafluorene-3-
carbonitrile (21b)
Yield, 80%, m.p. 237–239◦C, IR: ν = 3360–3340 (broad NH2), 2235
1
(C N), 1623 cm−1 (C N); H NMR (CDCl3): δ = 2.51 (s, 3H, SCH3),
3.89 (s, 3H, OCH3), 5.13 (s, 1H, pyran CH), 5.97 (br s, 2H, NH2), 6.91–
7.96 (m, 9H, ArH and oxazole H-2); anal. calcd. for C27H18BrN5O3S2:
C, 53.65; H, 3.00; N, 11.59%. Found: C, 53.76; H, 3.12; N, 11.47%.
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