A convenient synthesis and pharmacological activity of novel annelated pyrimidine derivatives

Article abstract of DOI:10.1002/jccs.200400202

Simple and convenient synthesis for a series of 2,3-diglycosylpyrimidine 4, 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, 1,3,5,7- tetraazafluorene-8-one 15, 1,3,5-triazafluor

Full text of DOI:10.1002/jccs.200400202

Journal of the Chinese Chemical Society, 2004, 51, 1381-1388
1381
A Convenient Synthesis and Pharmacological Activity of Novel Annelated
Pyrimidine Derivatives
A. A. Aly
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
Simple and convenient synthesis for a series of 2,3-diglycosylpyrimidine 4, 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, 1,3,5,7-
tetraazafluorene-8-one 15, 1,3,5-triazafluorene-8-one 16, 1,3-diazafluorene 21a,b derivatives have been syn-
thesized via a sequence of heterocyclization reactions of suitably functionalized 6-[5-(4-bromophenyl)ox-
azol-4-yl]-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (2) with different electrophiles and
nucleophiles. The new compounds were prepared with the objective to study their pharmacological proper-
ties.
Keywords: 2-Methylsulfanylpyrimidine; Pyrazolo[3,4-d]pyrimidine; Thieno[2,3-d]pyrimidine;
Azafluorenone.
INTRODUCTION
Pyrimidines and fused pyrimidines, being an integral
2-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosylsulfanyl)-3-
(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-3,4-dihydro-
pyrimidine-5-carbonitrile (4). The structure of compound 4
was confirmed on the bases of its elemental analysis and
spectral data. Its ir spectrum showed absence of NH group
and presence of absorption band at 1685 cm-1 due to the car-
bonyl of pyrimidinone in addition to the acetoxy carbonyl
groups at 1765-1750 cm-1. Also, the 1H NMR spectrum showed
the presence of eight OAc., and a doublet at d 5.60 with
spin-spin coupling constant 10.55 Hz which corresponds to
diaxial orientation of the H-1¢ and H-2¢ protons, indicating
the presence of only the b-configuration.17
part of DNA and RNA, play an essential role in several bio-
logical processes and have considerable chemical and phar-
macological importance. Particularly, the pyrimidine ring
can be found in the nucleoside antibiotics, antibacterial, anti-
tumor, cardiovascular as well as agrochemical and veterinary
products.1-9 In view of these observations and in continuation
of our interest in developing efficient syntheses of polyfunc-
tionally substituted heterocycles utilizing the readily obtain-
able pyrimidine as starting material,10-12 it is worthwhile to
explore their potential utility for synthesis of polyfunction-
ally substituted pyrimidine derivatives useful for optimiza-
tion of biological activity.
We then invested 2 in synthesis of S-alkylsulfanylpyr-
imidine derivatives which have been recently identified as
highly specific reverse transcriptase inhibitors of human im-
munodeficiency virus.18 Thus, the reaction of 2 with methyl
iodide in the presence of ethanolic sodium ethoxide solution
afforded 4-[5-(4-bromophenyl)oxazol-4-yl]-6-hydroxy-2-
methylsulfanylpyrimidine-5-carbonitrile (5) in good yield.
The electron deficient nature of the pyrimidine ring and
the high reactivity of the methylthio group towards nucleo-
philic reagents facilitate the synthesis of a large number of
condensed pyrimidine via nucleophilic aromatic substitu-
tion.19,20 Thus, reaction of 5 with POCl3/PCl5 on a water bath
yields 4-[5-(4-bromophenyl)oxazol-4-yl]-6-chloro-2-meth-
ylsulfanylpyrimidine-5-carbonitrile (6) which was used as a
precursor employed for synthesis of annelated pyrimidine of
RESULTS AND DISCUSSION
In the present work, 6-[5-(4-bromophenyl)oxazol-4-
yl]-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboni-
trile (2), required as a starting material, was conveniently pre-
pared from the reaction of 5-(4-bromophenyl)oxazole-4-
carbaldehyde (1)13 with ethyl cyanoacetate and thiourea.14,15
Reaction of 2 with 2,3,4,6-tetra-O-acetyl-a-D-glucopyr-
anosyl bromide (3)16 in the presence of aqueous potassium
hydroxide gave 6-[5-(4-bromophenyl)oxazol-4-yl]-4-oxo-
* Corresponding author. E-mail: alymaboud@hotmail.com

1382 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Aly
medicinal application. Hence, treatment of 6 with hydrazine
hydrate in refluxing 1-butanol for 2 hrs afforded 4-[5-(4-bro-
mophenyl)oxazol-4-yl]-2,6-dihydrazinopyrimidine-5-car-
bonitrile (7) which was further cyclized to pyrazolopyrimi-
dine 8 by refluxing in 1-butanol for 5 hrs. The formation of 8
proceeds via nucleophilic attack of the hydrazino moiety to
the cyano group in ortho position leading to fused pyrimidine
8. The ir spectrum of 8 displays lack of absorption of the
cyano group and presence of different bands in the region be-
tween 3340-3195 cm-1 (NH2 and NHNH2). Moreover, the
presence of latter groups was confirmed by the 1H NMR spec-
trum which consisted of a series of D2O exchangeable signals
that present different chemical shifts. Also, when an acidic
solution of 7 was allowed to react with an aqueous solution of
sodium nitrite at 0-5 °C ditetrazolo[1,5-a;1¢,5¢-c]pyrimidine
9 was obtained (Scheme I).
Treatment of 6 with thiourea21 in ethanolic solution
produced 4-[5-(4-(bromophenyl)oxazol-4-yl]-6-mercapto-
2-methylsulfanylpyrimidine-5-carbonitrile (10). Treatment
of 10 with anthranilic acid in 1-butanol afforded pyrimidine
derivative 11 which cyclized to 3-[5-(4-bromophenyl)ox-
azol-4-yl]-1-methylsulfanyl-9-oxo-9H-2,9a,10-triazaanthra-
cene-4-carbonitrile (12) by heating in acetic anhydride. Also,
the alkylation of 10 with ethyl chloroacetate in ethanolic so-
lution containing sodium acetate afforded S-alkylated deriva-
tive 13 which cyclized to thienopyrimidine derivative 14 in
ethanol containing sodium ethoxide. Of particular interest, a
cyclocondensation reactions of thienopyrimidine 14 with
Scheme I

Synthesis and Activity of Pyrimidine Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1383
phenyl isothiocyanate or by heating in acetic anhydride re-
sulted in the formation of tricyclic heterocycles 15 and 16, re-
spectively (Scheme II).
rene-7-carbonitrile (21a and 21b) (Scheme III). The structure
of the synthesized compounds was assigned on the basis of
elemental analysis and spectral data (cf. experimental).
Saponification of the o-aminoester 14 resulted in the
formation of the corresponding carboxylic acid 17 which
upon treatment with orthophosphoric acid at room tempera-
ture underwent decarboxylation22 to give amino compound
18. On the other hand, treating of 17 with orthophosphoric
acid at 100 °C, the product was identified as thienopyr-
imidine 19 which was also prepared via treatment of 18 with
orthophosphoric acid at 100 °C. The condensation of 19 with
aromatic aldehydes (viz. benzaldehyde and p-anisaldehyde)
in refluxing ethanol containing catalytic amounts of piper-
idine furnished the chalcones 20a and 20b, while the reaction
of 19 with arylmethylene malononitrile provided 6-amino-
4-[5-(4-bromophenyl)oxazol-4-yl]-2-methylsulfanyl-8-
(phenyl/4-methoxyphenyl)-8H-5-oxa-9-thia-1,3-diazafluo-
ANTIMICROBIAL ACTIVITY
The antimicrobial activities of some synthesized com-
pounds were determined in vitro using hole plate and filter
paper disc methods.23 A variety species of Gram positive and
Gram negative bacteria in addition to some fungal plant
pathogens were used. Also, a comparison between the activ-
ity of our synthesized compounds and sulphadiazine as stan-
dard drug was discussed. The tested compounds were dis-
solved in 10% acetone (v/v); different concentrations have
been chosen (125, 250, 500 mg/mL). A qualitative screen was
performed on all compounds while quantitative assays were
Scheme II
Ar
NH2
Ar
CN
COOH
N
NC
N
H2NCSNH2
CH3S
6
N
NH
SCH3
HS
N
HO
C
10
O
Ar
11
CN
N
N
Ac2O
N
CH3S
O
12
Ar
N
Ar
NH2
COOEt
EtONa
N
CN
N
ClCH2COOEt
AcONa
10
CH3S
S
CH3S
SCH2COOEt
N
14
13
i) NaOH
ii) Ac2O
PhNCS
Ar
Ar
N
H
N
N
O
CH3
S
Ph
N
N
O
CH3S
N
N
CH3S
S
S
O
15
16

1384 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Aly
Scheme III
14
i) NaOH
ii) AcOH
Ar
N
NH2
COOH
N
CH3S
S
17
H3PO4
r.t
H3PO4
o
100 C
Ar
Ar
NH2
O
N
H3PO4,
N
o
100 C
CH3S
CH3S
N
S
S
N
19
18
Ar`CH=C(CN)2
Ar
Ar`CHO
Ar
N
O
NH2
CN
O
N
N
CH3S
CH3S
CHAr`
N
S
S
Ar`
20a,b
21a,b
20,21: Ar`;
a = C6H5
b = p.OCH3
C H
6
4
done on active compounds only. The results are summarized
in Table 1.
The data indicated that most of the tested compounds 4,
5, 10, 15, 16, 21b were highly active towards the selected
Table 1. The antimicrobial activity of the tested compounds
Bacillus subtilis Bacillus cereus Escherichia coli Aspergillus niger
Compd. No.
A
MIC
A
MIC
A
MIC
A
MIC
4
5
9
+++
++
+
+++
+
++
+++
+++
++
++
++
500
250
500
250
250
250
500
250
125
125
250
+
+++
+
++
+
250
250
250
250
125
125
250
125
250
250
250
++
++
+
++
+
125
500
250
125
125
250
125
250
125
500
250
++
+
+
++
+
+
+
+
+
+
500
250
500
125
250
250
250
500
250
250
500
10
12
14
15
16
18
20a
21b
+
+
++
+++
+
+
++
++
++
+
++
+++
+
A = antimicrobial activity of tested compounds.
MIC = minimum inhibitory concentration.
+ > 5 mm slightly active.
++ > 7 mm moderately active.
+++ > 9 mm highly active.

Synthesis and Activity of Pyrimidine Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1385
pathogens, while the compounds 9, 12, 14, 18, 20a are mod-
erately active towards the different strains of bacteria and
fungi as compared with standards.
give 4. Yield, 58%, mp. 182-4 °C, IR: n = 2226 (CºN), 1765-
1750 (COCH3), 1685 (CO), 1618 (C=N), 1559 cm-1 (C=C);
1H NMR (DMSO): d = 1.77, 1.98, 2.06, 2.11, 2.15, 2.19, 2.21,
2.30 (8s, 24H, 8CH3CO), 3.70-4.28 (m, 6H, H-5¢, H-5², 2 ´
H-6¢, 2 ´ H-6²), 4.89-5.32 (m, 2H, H-4¢, H-4²), 5.40-5.48 (m,
4H, H-3¢, H-3², H-2², H-1²), 5.59 (t, 1H, J = 9.1 Hz, H-2¢),
5.60 (d, 1H, J = 10.55 Hz, H-1¢), 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%.
In summary, we have demonstrated the ability of py-
rimidine derivative 2 to undergo annelation reactions under
rather mild conditions providing an efficient synthetic method
for the preparation of various pyrimidine derivatives which
enhanced antibacterial and antifungal activity.
EXPERIMENTAL
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-hydroxy-2-methylsul-
fanylpyrimidine-5-carbonitrile (5)
Melting points are uncorrected. IR spectra in KBr were
recorded on a Perkin Elmer 298 spectrophotometer. 1H NMR
spectra were obtained on a Varian Gemini 200 MHz instru-
ment using TMS as internal reference (Chemical shifts are
expressed as d, ppm). Mass spectra were recorded on a
Shimidzu GCMS-QP 1000 EX instrument (70 ev EI mode).
All reactions were monitored by thin layer chromatography,
carried out on 0.2 mm silica gel 60 F254 (Merck) plates.
A solution of 2 (0.01 mol) and methyl iodide (0.01 mol)
in ethanolic sodium ethoxide (prepared by dissolving 1.0 gm
of sodium metal in 50 mL of ethanol). The reaction mixture
was cooled and poured onto ice-cold water. The solid product
obtained after acidification with hydrochloric acid was fil-
tered off, washed with water and crystallized from ethanol to
give 5. Yield, 85%, mp. 201-3 °C, IR: n = 3480 (OH), 2218
(CºN), 1615 (C=N), 1601 cm-1 (C=C); 1H NMR (CDCl3): d =
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%.
6-[5-(4-bromophenyl)oxazol-4-yl]-4-oxo-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carbonitrile (2)
A mixture of 5-(4-bromophenyl)oxazole-4-carbalde-
hyde (1)13 (0.01 mol), ethyl cyanoacetate (0.01 mol), thiourea
(0.01 mol), and potassium carbonate (0.01 mol) in absolute
ethanol (40 mL) was refluxed for 24 h. The precipitate which
formed after cooling and acidification was filtered off and
crystallized from DMF-water mixture to give 2.14,15 Yield,
52%, mp. 236-8 °C, IR: n = 3200-3190 (NH), 2221 (CºN),
1679 (CO), 1610 (C=N), 1265 cm-1 (CS); 1H NMR (DMSO):
d = 7.10-8.02 (m, 5H, ArH and oxazole H-2) and 11.7 (br s,
2H, 2NH exchangeable); 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%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-chloro-2-methylsul-
fanylpyrimidine-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 re-
action mixture was poured gradually on crushed ice and the
solid that separated was filtered off and crystallized from
benzene to give 6. Yield, 70%, mp. 195-7 °C, IR: n = 2223
(CºN), 1620 (C=N), 1603 cm-1 (C=C); 1H NMR (CDCl3): d =
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%.
6-[5-(4-Bromophenyl)oxazol-4-yl]-4-oxo-2-(2,3,4,6-tetra-
O-acetyl-b-D-glucopyranosylsulfanyl)-3-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)-3,4-dihydropyrimidine-5-car-
bonitrile (4)
4-[5-(4-Bromophenyl)oxazol-4-yl]-2,6-dihydrazinopyrimi-
dine-5-carbonitrile (7)
To a solution of 2 (0.001 mol) in aqueous potassium hy-
droxide (0.002 mol) in distilled water (10 mL) was added a
solution of 3 (0.0021 mol) in acetone (40 mL). The reaction
mixture was stirred for 4 h at room temperature until the start-
ing material was consumed (TLC). The mixture was evapo-
rated under reduced pressure and the residue was washed
with distilled water to remove the potassium bromide formed.
The solid product was dried and crystallized from ethanol to
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 crystal-
lized from 1-butanol to give 7. Yield, 78%, mp. 211-3 °C, IR:
n = 3330-3180 (NHNH2), 2219 (CºN), 1625 (C=N), 1601
1
cm-1 (C=C); H NMR (CDCl3): d = 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, 2H, 2NH, exchangeable); Anal. Calcd. for

1386 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Aly
C14H11BrN8O: C, 43.43; H, 2.86; N, 28.94%. Found: C,
43.55; H, 2.74; N, 28.82%.
(CºN), 1705 (CO), 1614 (C=N), 1598 cm-1 (C=C); 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%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-hydrazino-1H-pyr-
azolo[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 re-
moved at reduced pressure and the residue crystallized from
1-butanol to give 8. Yield, 88%, mp. 283-5 °C, IR: n = 3340-
3195 (NH2 and NHNH2), 1612 (C=N), 1605 cm-1 (C=C); 1H
NMR (DMSO): d = 5.68 (br s, 2H, NH2, exchangeable), 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%.
3-[5-(4-Bromophenyl)oxazol-4-yl]-1-methylsulfanyl-9-oxo-
9H-2,9a,10-triazaanthracene-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%, mp. 201-3 °C, IR: n = 2223 (CºN), 1680 (CO), 1615
1
cm-1 (C=N); H NMR (DMSO): d = 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%.
5-[5-(4-Bromophenyl)oxazol-4-yl]ditetrazolo[1,5-a;1¢,5¢-c]-
pyrimidine-6-carbonitrile (9)
Ethyl{6-[5-(4-bromophenyl)oxazol-4-yl]-5-cyano-2-methyl-
sulfanylpyrimidin-4-yl]sulfanyl}acetate (13)
A solution of sodium nitrite (0.0021 mol) in water (10
mL) was added to ice cooled water 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%, mp. 176-8 °C, IR: n = 2218 (CºN), 1614 (C=N), 1095-
1055 cm-1 (tetrazole ring); 1H NMR (DMSO): d = 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%.
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 reflux for 3 h. The precipitate that formed on
cooling was filtered and crystallized from benzene to yield 13.
Yield, 68%, mp. 211-3 °C, IR: n = 2218 (CºN), 1725 (CO),
1617 cm-1 (C=N); 1H NMR (CDCl3): d = 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-meth-
ylsulfanylthieno[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 ab-
solute 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 from ethanol to fur-
nish 14. Yield, 83%, mp. 187-9 °C, IR: n = 3320, 3300 (NH2),
1720 (CO), 1620 cm-1 (C=N); 1H NMR (CDCl3): d = 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%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-mercapto-2-methyl-
sulfanylpyrimidine-5-carbonitrile (10)
To a solution of chloropyrimidine 6 (0.0012 mol) in
ethanol (25 mL), thiourea (0.0012 mol) was added and the re-
action mixture was heated under reflux for 10 h. The solid ob-
tained after cooling was crystallized from ethanol to give 10.
Yield, 81%, mp. 190-2 °C, IR: n = 2370 (SH), 2216 (CºN),
1618 (C=N), 1601 cm-1 (C=C); 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, 13.71%.
2-{6-[5-(4-Bromophenyl)oxazol-4-yl)]-5-cyano-2-methyl-
sulfanylpyrimidin-4-ylamino}benzoic acid (11)
A mixture of 10 (0.011 mol) and anthranilic acid (0.011
mol) in 1-butanol was heated under reflux for 8 h. The reac-
tion mixture was then cooled and the solid obtained was fil-
tered off and crystallized from 1-butanol to yield 11. Yield,
73%, mp. 231-3 °C, IR: n = 3470-3205 (OH and NH), 2215
4-[5-(4-Bromophenyl)oxazol-4-yl]-2-methylsulfanyl-7-
phenyl-6-thioxo-6,7-dihydro-5H-9-thia-1,3,5,7-tetraaza-
fluorene-8-one (15)
To a solution of 14 (0.0011 mol) in pyridine (25 mL)

Synthesis and Activity of Pyrimidine Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1387
was added phenyl isothiocyanate (0.001 mol) and the reac-
tion mixture was refluxed in an oil bath for 20 h. The reaction
mixture after cooling was poured into ice/HCl and the solid
separated was filtered, washed with cold aqueous ethanol,
dried and crystallized from ethanol-DMF (2:1) to give 15.
Yield, 59%, mp. 214-6 °C, IR: n = 3280 (NH), 1680 (CO),
1621 (C=N), 1260 cm-1 (CS); 1H NMR (CDCl3): d = 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%.
lized from 1-butanol to afford 18. Yield, 72%, mp. 216-8 °C,
IR: n = 3360-3330 (broad NH2), 1621 (C=N), 1604 cm-1
(C=C); 1H NMR (CDCl3): d = 2.55 (s, 3H, CH3), 5.51 (br s,
2H, NH2), 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]pyrimidine-5-one (19)
Method a: A solution of 17 (0.0011 mol) in orthophos-
phoric acid 85% (30 mL) was heated on a water bath for 8 h.
The reaction mixture was poured on ice-water (50 mL) where
upon the solid formed; it was collected by filtration and crys-
tallized from toluene to give 19, yield 70%.
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-methyl-2-methylsul-
fanyl-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 of 14 in ethanolic sodium hy-
droxide solution for 2 h) in acetic anhydride (20 mL) was
heated under reflux for 3 h, then concentrated and allowed to
cool. The solid product was collected, washed with water and
crystallized from xylene to yield 16. Yield, 61%, mp. 226-8
Method b: A solution of 18 (0.0011 mol) in 85%
orthophosphoric acid (30 mL) was heated on a water bath 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 mp and mmp determina-
tion. Yield, 73%, mp. 207-9 °C, IR: n = 1698 (CO), 1622
(C=N), 1605 cm-1 (C=C); 1H NMR (CDCl3): d = 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%.
1
°C, IR: n = 1695 (CO), 1625 (C=N), 1602 cm-1 (C=C); H
NMR (CDCl3): d = 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-methylsul-
fanylthieno[2,3-d]pyrimidine-6-carboxylic acid (17)
A suspension of 14 (0.001 mol) in ethanolic sodium hy-
droxide solution 10% (50 mL) was heated under reflux for 4
h. The alkaline solution was acidified with diluted acetic acid
and extracted with ether. The solid separated after evapora-
tion of the dried ethereal layer was crystallized from ethanol
to furnish 17. Yield, 79%, mp. 241-3 °C, IR: n = 3475-3160
(OH and NH2), 1707 (CO), 1615 (C=N), 1602 cm-1 (C=C); 1H
NMR (DMSO): d = 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, exchangeable); Anal. Calcd. for C17H11BrN4O3S2: C,
44.07; H, 2.39; N, 12.09%. Found: C, 44.18; H, 2.50; N,
12.20%.
General procedure of the synthesis of 6-arylidene-4-[5-
(4-bromophenyl)oxazol-4-yl]-2-methylsulfanylthieno[2,3-
d]pyrimidine-5-one (20a,b)
A mixture of 19 (0.002 mol) and aromatic aldehydes
(0.0013 mol), namely benzaldehyde and/or p-anisaldehyde in
ethanol (25 mL) containing 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 fur-
nish 20a,b.
6-Benzylidene-4-[5-(4-bromophenyl)oxazol-4-yl]-2-methyl-
sulfanylthieno[2,3-d]pyrimidine-5-one (20a)
Yield, 89%, mp. 261-3 °C, IR: n = 1675 (CO), 1625-
1620 cm-1 (C=N); 1H NMR (CDCl3): d = 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]-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 (until the evolution of
CO2 gas ceased). The reaction mixture was poured on 80 mL
ice-water and then neutralized with 8% aqueous sodium car-
bonate. The solid product so formed was filtered and crystal-
4-[5-(4-Bromophenyl)oxazol-4-yl]-6-(4-methoxybenzyli-
dene)-2-methylsulfanylthieno[2,3-d]pyrimidine-5-one (20b)
Yield, 83%, mp. 283-4 °C, IR: n = 1680 (CO), 1624-

1388 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Aly
1620 cm-1 (C=N); 1H NMR (CDCl3): d = 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%.
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A mixture of 19 (0.0012 mol) and arylmethylene
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6-Amino-4[5-(4-bromophenyl)oxazol-4-yl]-2-methylsul-
fanyl-8-phenyl-8H-5-oxa-9-thia-1,3-diazafluorene-7-car-
bonitrile (21a)
Yield, 81%, mp. 273-5 °C, IR: n = 3350-3330 (broad
NH2), 2230 (CºN), 1620 cm-1 (C=N); 1H NMR (DMSO): d =
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 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%.
14. Kambe, S.; Saito, K.; Kishi, H.; Sakurai, A.; Midorikawa, H.
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6-Amino-4[5-(4-bromophenyl)oxazol-4-yl]-2-methylsul-
fanyl-8-(4-methoxyphenyl)-8H-5-oxa-9-thia-1,3-diazafluo-
rene-7-carbonitrile (21b)
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Yield, 80%, mp. 237-9 °C, IR: n = 3360-3340 (broad
NH2), 2235 (CºN), 1623 cm-1 (C=N); 1H NMR (CDCl3): d =
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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ACKNOWLEDGEMENT
All strains were kindly supplied from the Botany De-
partment, Faculty of Science, Benha University, Benha-
Egypt.
23. Leifert, C.; Chidbouree, S.; Hampson, S.; Workman, S.;
Sigee, D.; Epton, H. A.; Harbour, A. J. Appl. Bacteriol 1995,
78, 97.
Received April 8, 2004.