Synthesis and reactions of 5-amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin- 4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile

Article abstract of DOI:10.1007/s00706-007-0703-5

5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-phenyl-7H- thiazolo[3,2-a]pyrimidine-6-carbonitrile was synthesized via the reaction of 4-(2-aminothiazol-4-yl)-3-methyl-1-phenyl-2-pyrazolin-5-one with benzylidene malononitrile and was then transfor

Full text of DOI:10.1007/s00706-007-0703-5

Monatshefte fu¨r Chemie 138, 989–995 (2007)
DOI 10.1007/s00706-007-0703-5
Printed in The Netherlands
Synthesis and Reactions of 5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile
ꢀ
Mohamed Salah K. Youssef and Ahmed A. Omar
Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt
Received April 1, 2007; accepted (revised) April 24, 2007; published online July 20, 2007
# Springer-Verlag 2007
Summary. 5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazo-
lin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile
Results and Discussion
was synthesized via the reaction of 4-(2-aminothiazol-4-yl)-3-
Syntheses
methyl-1-phenyl-2-pyrazolin-5-one with benzylidene malono-
nitrile and was then transformed to related fused heterocyclic
systems. The antifungal and antibacterial studies revealed in
some cases excellent biocidal properties.
Compound 1 was prepared by reaction of 4-bromo-
acetyl-3-methyl-1-phenyl-2-pyrazolin-5-one with
thiourea. Then 1 was used as a candidate for the
synthesis of 5-amino-3-(3-methyl-5-oxo-1-phenyl-
2-pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrim-
idine-6-carbonitrile (2) and its fused derivatives.
For this purpose the target compound 2 was prepared
by interaction of 1 with benzylidenemalononitrile.
The reaction of 2 with phenyl isothiocyanate in
pyridine for 6 h provided 3-(3-methyl-5-oxo-1-phe-
nyl-2-pyrazolin-4-yl)-5-(N-phenylthiourea)-7-phenyl-
7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (3), but
when the reaction mixture was refluxed for 10 h
it gave 3,5-diphenyl-9-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-1,5-dihydro-4-imino-2-thioxo-2H-
pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine (4), the
latter compound could be also obtained by fusion
of 3 over its melting point.
Whereas the reaction of 2 with acetyl chloride
in the presence of pyridine as catalyst produced
5-acetylamino-3-(3-methyl-5-oxo-1-phenyl-2-pyra-
zolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyramidine-
6-carbonitrile (5), the acetylamino derivative was
also produced by the reaction of 2 with acetic
anhydride=pyridine (2=1 v=v) instead of 2-methyl-
9-(3-methyl-1-phenyl-2-pyrazolin-4-yl)-3,5-dihydro-
Keywords. Heterocycles; Pyrazolone; Thiazole; Thiazolo-
pyrimidine; Pyrimidothiazolopyrimidine.
Introduction
5-Pyrazolone is widely used as precursor for the syn-
thesis of different heterocycles with biological and
medicinal activities [1–5]. Heterocycles containing a
thiazole ring are associated with a particularly wide
range of biological properties including antiproto-
zoal [6] and anticonvulsants [7] activity as well as a
depressant effect on the central nervous system [8],
as antihelminthics [9], antidiabetics [10], and in-
hibitors of dihydrofolate [11]. In the present study
we report herein a simple synthesis method for the
preparation of 5-amino-3-(3-methyl-5-oxo-1-phenyl-
2-pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrim-
idine-6-carbonitrile (2) and its transformation to
related fused heterocyclic systems.
ꢀ
com
Corresponding author. E-mail: salah_kamel2000@yahoo.

990
M. S. K. Youssef and A. A. Omar
Scheme 1
5-phenyl-4H-pyrimido[5,4-e]thiazolo[3,2-a]pyrim-
idin-4-one. Also, the reaction of 2 with benzoyl
chloride gave 5-benzoylamino-3-(3-methyl-5-oxo-1-
phenyl-2-pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]-
pyrimidine-6-carbonitrile (6).
Treatment of 2 with malononitrile or ethyl
cyanoacetate gave 2,4-diamino-9-(3-methyl-5-oxo-
1-phenyl-2-pyrazolin-4-yl)-5-phenyl-5H-pyrimido-
[3,2-e]thiazolo[3,2-a]pyrimidine-3-carbonitrile (7)
or 4-amino-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-2-hydroxy-5-phenyl-5H-pyrido[3,2-e]thiazolo-
[3,2-a]pyrimidine-3-carbonitrile (8).
Refluxing 2 with formic acid gave 9-(3-methyl-5-
oxo-1-phenyl-2-pyrazolin-4-yl)-3,5-dihydro-5-phenyl-
4H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-4-one
(9). Reaction of nitrous acid with 2 under ordinary
conditions afforded 4-chloro-9-(3-methyl-5-oxo-1-
phenyl-2-pyrazolin-4-yl)-5-phenyl-5H-thiazolo[20,30:
2,3]pyrimido[4,5-d][1,2,3]triazine (10) while the
reaction of 2 with formamide provided 4-amino-9-

Substituted 7H-Thiazolo[3,2-a]pyrimidine-6-carbonitrile
991
Scheme 2
(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-phenyl-
5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine (11).
The reaction of 2 with excess of triethyl ortho-
formate led to the formation of 5-(ethoxymethylene-
amino)-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-
yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbo-
nitrile (12). Attempts to cyclize 12 by stirring in
absolute ethanol containing an excess hydrazine
hydrate afforded 3-amino-9-(3-methyl-5-oxo-1-phe-
nyl-2-pyrazolin-4-yl)-3,5-dihydro-4-imino-5-phenyl-
4H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine (13).
Carbon disulfide reacted with 2 in pyridine to give
9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-
phenyl-2, 4-dithioxo-1, 3, 4, 5-tetrahydro-2H-pyrim-
ido[5,4-e]thiazolo[3,2-a]pyrimidine (14), which on
subsequent alkylation with ethyl iodide afforded
2,4-bis(ethylthio)-9-(3-methyl-5-oxo-1-phenyl-2-py-
razolin-4-yl)-5-phenyl-5H-pyrimido[5,4-e]thiazolo-
[3,2-a]pyrimidine (15). Also, on refluxing 2 with
trichloroacetonitrile in toluene in presence of a
catalytic amount of piperidine yields 4-amino-9-(3-
methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-2-trichloro-
methyl-5-phenyl-5H-pyrimido[5,4-e]thiazolo[3,2-a]-
pyrimidine (16), the trichloro moiety in 16 could
be substituted by a hydroxyl group on refluxing
with aqueous sodium hydroxide solution, and by an
ethoxy group on boiling with sodium ethoxide
in ethanol to give 4-amino-2-hydroxy-9-(3-methyl-
5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-phenyl-5H-py-
rimido[5,4-e]thiazolo [3,2-a]-pyrimidine (17) and
4-amino-2-ethoxy-9-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-5-phenyl-5H-pyrimido[5,4-e]thiazolo-
[3,2-a]pyrimidine (18).
The structure of new compounds was confirmed
on the basis of elemental analyses as well as spectral
1
data (IR, H NMR, and MS).
Biological Activity
Some of the prepared compounds were tested for
their antimicrobial activity against six fungal and
five bacterial species (Table 1). Compounds 15 and
17 showed a wide spectrum of antifungal action but
a narrow spectrum of antibacterial effect with mini-
mum inhibitory concentrations (MIC) ranging from
5–50 mg=cm3 (Table 1). Compound 13 was only ef-
fective against three fungal species including Asper-
gillus flavus, Aspergillus niger, and Trichophyton

992
M. S. K. Youssef and A. A. Omar
Scheme 3
Table 1. The minimum inhibitory concentrations of the compounds tested (mg=cm3)
Organisms Compounds
ꢀ
2
3
4
7
8
11
12
13
15
17
Ref.
Fungi
Aspergillus flavus
Aspergillus niger
Candida albicans
Geotrichum candidum
Scopulariopsis brevicaulis
Trichophyton rubrum
–
–
20
20
–
–
–
–
–
–
–
–
–
–
50
–
50
–
–
–
–
–
10
–
–
–
–
–
10
–
–
–
–
–
10
–
–
20
20
–
–
–
20
20
20
20
10
–
–
50 (p.i.)
50
10
10
10
10
10
10
–
50 (p.i.)
20
50
50
–
–
–
20
Bacteria
Bacillus cereus (Gram positive)
20
20
–
20
–
50
–
–
–
–
50
–
–
–
–
–
–
–
50
–
–
50
–
–
–
–
–
–
–
50
2
5
–
–
–
–
–
–
–
–
2
5
–
–
–
10
10
5
–
–
10
10
10
10
10
Staphylococcus aureus (Gram positive)
Pseudomonas aeruginosa (Gram negative)
Serratia marcescens (Gram negative)
Escherichia coli (Gram negative)
ꢀ
– No antimicrobial action
p.i. Partial inhibition
Ref. Reference drugs ¼ chloramphenicol as antibacterial and clotrimazole as antifungal

Substituted 7H-Thiazolo[3,2-a]pyrimidine-6-carbonitrile
993
to give 4.10g (75%) 1. Mp 234ꢃC; 1H NMR (90 MHz,
DMSO-d6): ꢁ ¼ 2.90 (s, CH3), 5.01 (s, NH2), 7.11 (s, thiazole-
H), 7.41–8.10 (m, Ar–H, pyrazole-H) ppm; IR (KBr):
ꢀꢀ¼ 3300, 3400 (NH2), 3100 (CH aliphatic), 1705 (C¼O)
cmꢂ1; MS (70 ev): m=z (%) ¼ 271.78 (Mþ, 100).
rubrum. The remaining compounds exhibited a nar-
row spectrum of antimicrobial action. Their inhibitory
effect was often confined to the fungus Geotrichum
candidum, and Gram positive bacteria Bacillus
cereus and Staphylococcus aureus with MIC ranging
from 2 to 50mg=cm3. It is to be mentioned that Gram
negative bacteria Escherichia coli, Pseudomonas
aeruginosa, and Serratia marcescens were generally
resistant to the compounds tested. Exceptions were
observed with P. aeruginosa, which was inhibited by
17 (MIC 5 mg=cm3). S. marcescens was suppressed
by compounds 2 and 7 which were effective at con-
centrations ranging from 20 to 50 mg=cm3. Among
the tested fungi G. candidum was the most sensitive
organism to the compounds tested. As shown in
Table 1, Candida albicans and T. rubrum were only
sensitive to four out of the ten compounds. A. niger
was inhibited by three compounds. A. flavus and
S. brevicaulisulis showed sensitivity towards two of
the compounds tested. Comparing the MIC of the
effective compounds with those of the reference
drugs (chlotrimazole as antifungal and chloramphen-
icol as antibacterial) revealed that compound 12
was effective against Gram positive bacteria at con-
centrations ranging from 2 to 5 mg=cm3 which are
comparatively lower than the MIC of chlorampheni-
col (10 mg=cm3), also compound 17 was effective
against P. aeruginosa at 5 mg=cm3. Otherwise the
MIC of the antimicrobial compounds were equal or
higher than those of the reference drugs.
5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-
phenyl-7H-thiazolo[3,2-a]pyramidine-6-carbonitrile
(2, C23H18N6OS)
A mixture of 3.30 g 1 (12 mmol) and 1.80g benzylidene mal-
ononitrile (12 mmol) in 50cm3 absolute ethanol containing
0.5 cm3 triethylamine was refluxed for 7 h, then cooled and
poured into cold water, and the solid thus formed was filtered
off, washed several times with water, and recrystallized
1
from benzene to give 3.70g (73%) 2. Mp 225ꢃC; H NMR
(400MHz, CDCl3): ꢁ ¼ 2.21 (s, CH3), 4.50 (s, NH2), 7.09 (s,
thiazole-H), 6.11 (s, pyrimidine-H), 7.30 (s, pyrazole-H), 7.40–
8.20 (m, Ar–H) ppm; IR (KBr): ꢀꢀ¼ 3215, 3425 (NH2), 2175
(CN), 1705 (C¼O) cmꢂ1; MS (70 ev): m=z (%) ¼ 425.69
(Mþ, 72.4).
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5(N-
phenylthiourea)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-
6-carbonitrile (3, C30H23N7OS2)
A mixture of 1.23g 2 (2.8mmol) and 0.36cm3 phenyl isothio-
cyanate (2.8mmol) in 20cm3 pyridine was refluxed for 6 h,
poured into ice water, filtered off, dried, and recrystallized
1
from ethanol to afford 0.96g (75%) 3. Mp 215ꢃC; H NMR
(90 MHz, DMSO-d6): ꢁ ¼ 2.21 (s, CH3), 6.11 (s, pyrimidine-
H), 7.11 (s, thiazole-H), 7.21–8.20 (m, Ar–H, pyrazole-H),
9.20 (s, NH), 10.31 (s, NH) ppm; IR (KBr): ꢀꢀ¼ 3400 (NH),
2200 (CN), 1705 (C¼O), 1500 (C¼S) cmꢂ1
.
3,5-Diphenyl-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-
1,5-dihydro-4-imino-2-thioxo-2H-pyrimido[5,4-e]thiazolo-
[3,2-a]pyrimidine (4, C30H23N7OS2)
A mixture of 1.23g 2 (2.8mmol) and 0.36cm3 phenyl isothio-
cyanate (2.8mmol) in 20cm3 pyridine was refluxed for 10h,
poured into ice water, filtered off, dried, and recrystallized
Experimental
Melting points were determined on APP. Digital ST 15 melt-
ing point apparatus. Elemental analyses (C, H, N, and S) were
conducted using a Vario EL C, H, N, and S Analyzer; their
results were found to be in good agreement (ꢁ0.3%) with the
calculated values. The IR spectra were obtained on a Pye-
Unicam SP 3-100 spectrophotometer using the KBr disc
1
from ethanol to give 0.93g (73%) 4. Mp 260ꢃC; H NMR
(90 MHz, CDCl3): ꢁ ¼ 2.20 (s, CH3), 4.30 (s, imino-H), 6.10
(s, pyrimidine-H), 7.11 (s, thiazole-H), 9.91 (s, NH), 7.31–
7.81 (m, Ar–H, pyrazole-H) ppm; IR (KBr): ꢀꢀ¼ 3400 (NH),
1705 (C¼O), 1600 (C¼N), 1505 (C¼S) cmꢂ1, disappearance
of CN group.
1
technique (ꢀꢀmax in cmꢂ1). H NMR spectra were recorded
on JNMFT 400 Lambda series and EM 390 NMR spectrom-
eter, chemical shifts were given in ppm in a suitable deuterat-
ed solvent using TMS as an internal standard and the mass
spectra were run on JOEL JMS 600 spectrometer.
An Alternative Route for the Preparation of 4
One gram of 3 was fused over its melting point (225ꢃC) for
2 h, then cooled; and the solid product thus formed was recrys-
tallized from ethanol to give dark red powder of 4. It was found
that the compound 4 was identical with that prepared above.
4-(2-Aminothiazol-4-yl)-3-methyl-1-phenyl-2-pyrazolin-5-one
(1, C13H12N4OS)
A mixture of 6.00 g 4-bromoacetyl-3-methyl-1-phenyl-2-pyr-
azolin-5-one (20 mmol) and 1.52g thiourea (20 mmol) in
100 cm3 absolute ethanol was refluxed for 5 h. The reaction
mixture was concentrated, cooled, and neutralized with sodi-
um acetate solution (6%). The precipitated solid was filtered
off, washed with water, dried, and crystallized from benzene
5-Acetylamino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-
7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile
(5, C25H20N6O2S)
A mixture of 1.00 g 2 (2.3 mmol) and 5 cm3 acetyl chlo-
ride in 10 cm3 pyridine was refluxed for 3 h. The reaction

994
M. S. K. Youssef and A. A. Omar
mixture was cooled and poured into cold water, then the
solid product was filtered off and recrystallized from ben-
zene to give 0.87 g (81%) 5. Mp 245ꢃC; 1H NMR
(90 MHz, CDCl3): ꢁ ¼ 2.21 (s, CH3), 2.41 (s, CH3 of ace-
tyl), 6.10 (s, pyrimidine-H), 7.11 (s, thiazole-H), 7.30–8.62
(m, Ar–H, pyrazole-H), 10.31 (s, NH) ppm; IR (KBr):
ꢀꢀ¼ 3200 (NH), 2200 (CN), 1705 (C¼O), 1680 (C¼O of
ppm; IR (KBr):
(C¼O) cmꢂ1
ꢀꢀ¼ 3300, 3400 (NH2), 2200 (CN), 1710
.
9-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-3,5-dihydro-
5-phenyl-4H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-4-one
(9, C24H18N6O2S)
A mixture of 1.23g 2 (2.8mmol) and 3 cm3 formic acid
(6.5mmol) was refluxed for 5 h. The reaction mixture was
poured into cold water whereby the product thus formed
was separated, filtered off, dried, and recrystallized from tolu-
acetamide) cmꢂ1
.
An Alternative Route for the Preparation of 5
A mixture of 1.23g 2 (2.8mmol) in 30 cm3 acetic anhydride=
pyridine mixture (2=1 v=v) was heated under reflux for
4 h. The reaction mixture was cooled and poured into cold
water, then the solid product was filtered off and recrystal-
lized from ethanol to give yellow crystals of 5. It was
found that the compound 5 was identical in all aspects (mp,
mixed mp, IR, and 1H NMR) with that prepared from 2 with
acetyl chloride.
1
ene to afford 1.04g (80%) 9. Mp 260ꢃC; H NMR (90 MHz,
DMSO-d6): ꢁ ¼ 2.30 (s, CH3), 6.10 (s, pyrimidine-H), 7.10 (s,
thiazole-H), 7.30–7.70 (m, Ar–H, pyrazole-H), 10.30 (s, NH)
ppm; IR (KBr): ꢀꢀ¼ 3300 (NH), 1705 (C¼O), 1640 (C¼O of
pyrimidine) cmꢂ1; MS (70 ev): m=z (%) ¼ 454.38 (Mþ, 72.4).
4-Chloro-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-
phenyl-5H-thiazolo[20,30:2,3]pyrimido[4,5-d][1,2,3]triazine
(10, C23H16N7OSCl)
To a mixture of 1.23 g 2 (2.8 mmol) and 3 cm3 hydrochloric
acid, a solution of 0.016 g sodium nitrite (2.8mmol) in 5 cm3
cold water was added with stirring at 5ꢃC. After com-
plete addition of sodium nitrite solution, the product was
precipitated, then collected by filtration, and crystallized
5-Benzoylamino-3-(-3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-
yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile
(6, C30H22N6O2S)
A mixture of 1.00 g 2 (2.3mmol) and 5 cm3 benzoyl chloride
in 10 cm3 pyridine was refluxed for 3 h. The reaction mixture
was cooled and treated with 50 cm3 petroleum ether (60–
80ꢃC) whereby solid product was separated, collected by
filtration, and recrystallized from ethanol to give 0.93 g
1
from ethanol to give 0.94 g (70%) 10. Mp 280ꢃC; H NMR
(90 MHz, DMSO-d6): ꢁ ¼ 2.20 (s, CH3), 6.10 (s, pyrimidine-
H), 7.10 (s, thiazole-H), 7.31–7.70 (m, Ar–H, pyrazole-H)
ppm; IR (KBr): ꢀꢀ¼ 1705 (C¼O) cmꢂ1, disappearance of CN
and NH2 groups.
1
(75%) 6. Mp 250ꢃC; H NMR (90 MHz, CDCl3): ꢁ ¼ 2.20
(s, CH3), 6.10 (s, pyrimidine-H), 7.10 (s, thiazole-H), 7.30–
7.80 (m, Ar–H, pyrazole-H), 10.20 (s, NH) ppm; IR (KBr):
ꢀꢀ¼ 3300 (NH), 2200 (CN), 1710 (C¼O), 1630 (C¼O of
4-Amino-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-
phenyl-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine
(11, C24H19N7OS)
benzamide) cmꢂ1
.
A mixture of 1.23g 2 (2.8mmol) and 3 cm3 formamide was
refluxed for 4 h, then cooled and poured into ice-water mix-
ture. The precipitate thus formed was collected by filtration,
washed several times with water, and crystallized from ben-
2,4-Diamino-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-
5-phenyl-5H-pyrido[3,2-e]thiazolo[3,2-a]pyrimidine-3-
carbonitrile (7, C26H20N8OS)
A mixture of 1.00g 2 (2.3 mmol) and 0.15 g malononitrile
(2.3mmol) in 20 cm3 pyridine was refluxed for 4 h. The re-
action mixture was cooled and poured into cold water where-
by solid product was separated, filtered off, and recrystallized
1
zene to give 0.74g (70%) 11. Mp 217ꢃC; H NMR (90 MHz,
CDCl3): ꢁ ¼ 2.40 (s, CH3), 4.30 (s, NH2), 6.10 (s, pyrimidine-
H), 7.10 (s, thiazole-H), 7.40–7.70 (m, Ar–H, pyrazole-H)
,
1
from benzene to afford 0.77g (67%) 7. Mp 300ꢃC; H NMR
ppm; IR (KBr): ꢀꢀ¼ 3215–3420 (NH2), 1705 (C¼O) cmꢂ1
(90 MHz, DMSO-d6): ꢁ ¼ 2.20 (s, CH3), 4.90 (s, 2NH2), 6.10
(s, pyrimidine-H), 7.10 (s, thiazole-H), 7.30–7.80 (m, Ar–H,
pyrazole-H) ppm; IR (KBr): ꢀꢀ¼ 3300, 3400 (NH2), 2200
disappearance of CN group; MS (70 ev): m=z (%) ¼ 454.09
(Mþ, 82.4).
(CN), 1710 (C¼O) cmꢂ1
.
5-(Ethoxymethyleneamino)-3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-
carbonitrile (12, C26H22N6O2S)
4-Amino-2-hydroxy-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-5-phenyl-5H-pyrido[3,2-e]thiazolo[3,2-a]pyrimidine-
3-carbonitrile (8, C26H19N7O2S)
A mixture of 1.23g 2 (2.8mmol) and 5 cm3 triethyl orthofor-
mate (30 mmol) was heated under reflux for 7 h. After cooling
the reaction mixture was poured into cold water and the solid
product thus formed was filtered off, dried, and recrystallized
from benzene to afford 1.00 g (74%) 12. Mp 263ꢃC; 1H NMR
(90 MHz, DMSO-d6): ꢁ ¼ 1.20 (t, CH3), 1.90 (q, CH2), 2.20 (s,
CH3 of pyrazole), 4.10 (s, CH¼N), 6.10 (s, pyrimidine-H),
7.10 (s, thiazole-H), 7.30–7.80 (m, Ar–H, pyrazole-H) ppm;
A mixture of 1.00 g 2 (2.3 mmol) and 0.26 cm3 ethyl cya-
noacetate (2.3 mmol) in 20 cm3 pyridine was refluxed for
4 h. The reaction mixture was cooled and poured into cold
water whereby solid product was separated, filtered off,
and recrystallized from benzene to give 0.75 g (65%) 8.
Mp 310ꢃC; 1H NMR (90 MHz, DMSO-d6): ꢁ ¼ 2.20 (s,
CH3), 4.90 (s, NH2), 6.10 (s, pyrimidine-H), 7.10 (s, thia-
zole-H), 7.30–7.80 (m, Ar–H, pyrazole-H), 9.50 (s, OH)
IR (KBr): ꢀꢀ¼ 2200 (CN), 1705 (C¼O), 1590 (C¼N) cmꢂ1
;
MS (70 ev): m=z (%) ¼ 481.19 (Mþ, 25.4).

Substituted 7H-Thiazolo[3,2-a]pyrimidine-6-carbonitrile
995
3-Amino-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-3,5-
dihydro-4-imino-5-phenyl-4H-pyrimido[5,4-e]thiazolo-
[3,2-a]pyrimidine (13, C24H20N8OS)
4-Amino-2-hydroxy-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-5-phenyl-5H-pyrimido[5,4-e]thiazolo[3,2-a]-
pyrimidine (17, C24H19N7O2S)
A mixture of 0.70 g 12 (1.4mmol) and 2 cm3 hydrazine hy-
drate (40 mmol) in absolute ethanol was stirred at rt for 24h.
The precipitated product was collected by filtration and re-
crystallized from absolute ethanol to give 0.53 g (78%) 13.
Mp 285ꢃC; 1H NMR (90 MHz, DMSO-d6): ꢁ ¼ 2.20 (s, CH3),
4.30 (s, imino-H), 4.80 (s, NH2), 6.10 (s, pyrimidine-H), 7.10
(s, thiazole-H), 7.80–7.90 (m, Ar–H, pyrazole-H) ppm; IR
(KBr): ꢀꢀ¼ 3400 (NH2), 3500 (NH), 1705 (C¼O), 1595
(C¼S) cmꢂ1, disappearance of CN group; MS (70 ev): m=z
(%) ¼ 467.95 (Mþ, 65.4).
A mixture of 0.50 g 16 (0.87 mmol) and solution of 0.50g
sodium hydroxide in 5 cm3 H2O was refluxed for 0.5 h. The
product obtained was collected by filtration and recrystallized
1
from ethanol to give 0.29g (72%) 17. Mp 293ꢃC; H NMR
(90 MHz, DMSO-d6): ꢁ ¼ 2.20 (s, CH3), 4.92 (s, NH2), 6.10
(s, pyrimidine-H), 7.10 (s, thiazole-H), 7.40–7.70 (m, Ar–H,
pyrazole-H) ppm; IR (KBr): ꢀꢀ¼ 3300 (NH2), 3400 (OH),
1710 (C¼O) cmꢂ1
.
4-Amino-2-ethoxy-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-5-phenyl-5H-pyrimido[5,4-e]thiazolo[3,2-a]-
9-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-phenyl-
2,4-dithioxo-1,3,4,5-tetrahydro-2H-pyrimido[5,4-e]thiazolo-
[3,2-a]pyrimidine (14, C24H18N6OS3)
pyrimidine (18, C26H23N7O2S)
A mixture of 0.50 g 16 (0.87 mmol) and sodium ethoxide
(0.1g Na=10cm3 absolute ethanol) was refluxed for 0.5 h.
After cooling, the precipitated solid was collected by filtra-
tion and recrystallized from dioxane to give 0.30 g (69%) 18.
Mp 290ꢃC; 1H NMR (90 MHz, DMSO-d6): ꢁ ¼ 1.30 (t, CH3),
2.40 (s, CH3), 3.10 (q, CH2), 4.90 (s, NH2), 6.10 (s, pyrimi-
dine-H), 7.10 (s, thiazole-H), 7.40–7.90 (m, Ar–H, pyrazole-
A mixture of 4.26g 2 (10 mmol) and 5 cm3 carbon disulfide
(10 mmol) was heated on a water bath for 8 h. The reaction
mixture was poured into cold water and the solid product thus
formed was filtered off, dried, and recrystallized from benzene
to give 3.5 g (70%) 14. Mp 250ꢃC; 1H NMR (400 MHz,
DMSO-d6): ꢁ ¼ 2.40 (s, CH3), 6.10 (s, pyrimidine-H), 7.10
(s, thiazole-H), 7.11–7.40 (m, Ar–H, pyrazole-H), 7.90 (s,
2NH) ppm; IR (KBr): ꢀꢀ¼ 3200 (NH), 1710 (C¼O), 1540–
1570 (C¼S) cmꢂ1; MS (70 ev): m=z (%) ¼ 501.09 (Mþ, 82.4).
H) ppm; IR (KBr): ꢀꢀ¼ 3200 (NH2), 1705 (C¼O) cmꢂ1
.
Acknowledgement
We are grateful to Assiut University Mycology Center (AUMC)
for biological analyses.
2,4-Bis(ethylthio)-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-5-phenyl-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine
(15, C28H26N6OS3)
A mixture of 0.50 g 14 (9.9mmol) and 1.00 cm3 ethyl iodide
(9.9mmol) in 20 cm3 absolute ethanol in the presence of
1.50g anhydrous sodium acetate was refluxed for 3 h. The
solid product thus precipitated was collected by filtration
and recrystallized from ethanol to give 0.38 g (70%) 15. Mp
References
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1
235ꢃC; H NMR (90 MHz, DMSO-d6): ꢁ ¼ 1.30 (t, 2CH3),
2.20 (s, CH3), 4.20 (q, 2CH2), 6.10 (s, pyrimidine-H), 7.20
(s, thiazole-H), 7.30–8.10 (m, Ar–H, pyrazole-H) ppm; IR
(KBr): ꢀꢀ¼ 2950 (CH aliphatic), 1705 (C¼O) cmꢂ1
.
4-Amino-9-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-2-
trichloromethyl-5-phenyl-5H-pyrimido[5,4-e]thiazolo[3,2-a]-
pyrimidine (16, C25H18N7OSCl3)
A mixture of 4.26g 2 (10 mmol) and 1.00 cm3 trichloroaceto-
nitrile (10 mmol) was refluxed in 25 cm3 dry toluene contain-
ing a catalytic amount of piperidine for 3 h. The product which
was separated during the reflux was filtered off, dried, and
recrystallized from dioxane to give 4.35 g (76%) 16. Mp
300ꢃC; 1H NMR (90 MHz, DMSO-d6):ꢁ ¼ 2.40 (s, CH3),
4.90 (s, NH2), 6.10 (s, pyrimidine-H), 7.10 (s, thiazole-H),
7.40–7.90 (m, Ar–H, pyrazole-H) ppm; IR (KBr): ꢀꢀ¼ 3100,
3200 (NH2), 1705 (C¼O) cmꢂ1, disappearance of CN group.
[10] Raeymakers AHM, Alleuigin FTN, Vandenherk J,
Domoen PJA, Ottenwert TTT, Janssen PAJ (1966) J
Med Chem 9: 545
[11] Hurbert BS, Perone R, Hermann TA, Hitchings GH
(1968) J Med Chem 11: 711