Studies with S-alkylpyrimidine: New route for the synthesis derivatives of isoxazol, pyrazolo[1,5-a]pyrimidine, pyridazine, pyridine, thieno[2,3-b]pyridine and thiophene of potential anti-HIV

Article abstract of DOI:10.1002/jhet.5570450417

(Chemical Equation Presented) Derivatives of thiophene, thieno[2,3-b]pyridine, pyridine, isoxazol, pyrazolo[1,5-a]pyridine, pyridazine linked with s-pyrimidine derivative have been synthesized and tested for antimicrobial and antifungal activities. The structure of the newly synthesized compounds have been established on the basis of their analytical and spectral data.

Full text of DOI:10.1002/jhet.5570450417

Jul-Aug 2008
1057
Studies with S-Alkylpyrimidine: New Route for the Synthesis
Derivatives of Isoxazol, Pyrazolo[1,5-a]pyrimidine, Pyridazine,
Pyridine, Thieno[2,3-b]pyridine and Thiophene of Potential Anti-HIV
Fatima A. Al-Omran* and Adel A. El-Khair
Chemistry Department, Faculty of Science, Kuwait University,
P. O. Box 5969, 13060 Safat, Kuwait.
Received July 7, 2007
NH2
Me
S
N
N
N
S
N
H
Me
NH
N
N
S
YCH2CN
pip.EtOH, reflux
N
N
S
S
NMe2
Me
X
EtOH, reflux
Me
N
N
S
N
Y=CN, CSNH2
CN
X=O
O
Me
X=S
Derivatives of thiophene, thieno[2,3-b]pyridine, pyridine, isoxazol, pyrazolo[1,5-a]pyridine, pyridazine
linked with s-pyrimidine derivative have been synthesized and tested for antimicrobial and antifungal
activities. The structure of the newly synthesized compounds have been established on the basis of their
analytical and spectral data.
J. Heterocyclic Chem., 45, 1057 (2008).
INTRODUCTION
behaviour of pyrimidine-2(1H)-thione 1 which has been
reported earlier from our laboratories [8] towards a
variety of chemical reagents in applied to obtained a
series of compounds where a sulfur atom links the
pyrimidine with other heteroaromatic rings such as
2-aminothiophene, thieno[2,3-b]pyridine, pyridine, pyra-
zolo[1,5-a]pyrimidine and pyridazine derivatives (V) in
the hope of obtaining compounds of potential anti HIV.
The importance of the above compounds is due to their
diverse pharmaceutical activities [9-12].
Driven by increased demand for anti-HIV and antiviral
drugs, the search for new heterocyclic compounds and
novel methods of their synthesis is a major topic in
contemporary synthesis. A variety of thiols have been
synthesised and tested against non-nucleoside reverse
transcriptase inhibitors (NNRTIs) resistant HIV
infections. Among the numerous compounds showing
such reactivity as 1-[(2-hydroxyethoxy)methyl]-6-
(phenylthio)thymine (I) (HEPT), pyridinones (II), 8-
heteroarylthiomethyldipyridodiazepinone (III) and tri-
substituted triazoles (IV) [1-3].
RESULTS AND DISCUSSION
The key intermediate of S-alkylated derivative 2 used in
our experiments has been prepared in excellent yield by
treatment of pyrimidine-2(1H)-thione 1 with ꢀ-chloro-
acetone in refluxing acetone containing anhydrous
potassium carbonate. The structure of S-alkylated
derivative 2 was established on the basis of its elemental
analysis and spectral data. The mass spectrum of 2
O
O
R1
R1
R2
HN
R3
HN
S
S
O
N
R2
O
RO
R3
(II)
(I)
1
revealed a molecular ion peak with m/z 250. The H nmr
of 2 revealed in addition to thiophene and pyrimidine
rings protons, two singlet signals at ꢁH 2.34 and 4.21 ppm
due to corresponding methyl and methylene protons
respectively. The ir spectrum of 2 revealed CO stretching
bands at ꢂmax 1716 cmꢀ1. Moreover, 13C nmr spectrum
revealed highest frequency signal at ꢁC 203.0 ppm
assignable to the carbonyl carbon.
H
N
O
O
N
N
N
N
R
R1
R
N
S
Cl
N
S
N
To study the behaviour of S-alkylated derivative 2
towards carbon nucleophiles in order to produce new
polyfunctional substituted thiophene derivatives, where
thiophene nucleus linked directly to a pyrimidine ring
through, an S-linkage in hope of discovering compound of
potential anti HIV agents. Therefore, 2-aminothiophene-
(III)
(IV)
In conjunction with previous interest in the synthesis of
polyfunctionally substituted heterocycles with potential
biological activities [4-7], it was interesting to study the

1058
F. A. Al-Omran and A. A. El-Khair
Vol 45
3-carbonitrile derivative 3 used in our experiments has
been prepared according to Gawald's reaction [13] in situ
via a one-step process by treatment of S-alkylated
derivative 2 with malononitrile in refluxing ethanol and in
the presence of elemental sulfur containing a catalytic
amount of triethylamine to gave a product that could be
formulated as 3 or its isomers 4. The mass spectrum of
reaction product revealed a molecular ion peak with m/z at
330. However, the presence of methyl singlet at ꢀ 2.12
ppm in the 1H nmr spectrum indicate that methylene
carbon in S-alkylated 2 is involved in the reaction which
readily excluded the possibility of 4. Moreover, the ir
spectrum of 3 revealed the presence of amino stretching at
reflux temperature gives the enaminone 6 in a good yield.
The structure of enaminone was confirmed on the basis of
elemental analysis and spectral data. The mass spectrum
of compound 6 revealed a molecular ion peak with m/z
305. 1H nmr revealed three upfield signals at ꢀH 2.13,
3.14 and 3.16 ppm corresponding to methyl and two N,N-
dimethylamino protons respectively in addition to the one
signal downfield at ꢀH 8.08 ppm corresponding to =CH
proton (H-4) (cf. Scheme 1).
The reactivity of the enaminone 6 toward active
methylene nitrile was investigated. Thus, treatment of 6
with malononitrile in the refluxing ethanol containing a
catalytic amount of piperidine yielded a product that
could be formulated as 7 or it is isomer 8. The initial
condensation product yield from the reaction 6 with
malononitrile failed to react with elemental sulfur in a
mixture of DMF/EtOH containing a catalytic amount of
piperidine to obtain the thienopyridine derivative 9, as is
characteristic of azines with vicinal methyl and
carbonitrile substituents [14]. The structure 8 was ruled
out and the product assigned to be structure 7. The
formation of compound 7 is considered most likely based
on its similarity to well established behaviour, which was
assumed to proceed via initial Michael addition of active
methylene reagent across double bond in enaminone 6
that cyclize and undergo Dirmoth type rearrangement
followed by aromatisation via loss a hydrogen and
dimethylamine molecules to yield the final product 7 [15].
In a similar manner, compound 6 reacted also with
cyanothioacetamide in refluxing ethanol containing a
catalytic amount of piperidine to give a high yield of
crystalline product for which structure 10 was assigned on
ꢁ
max 3421-3329 cmꢀ1 in addition to cyano group stretching
at ꢁmax 2201 cmꢀ1. The absence of carbonyl group
absorption in the ir spectrum, indicates also that the
carbonyl group is involved in the reaction.
On the other hand, treatment of 3 with benzylidene-
malononitrile in refluxing pyridine afforded 3,4-dihydro-
thieno[2,3-b]pyridine derivative 5 in good yield. The
structure of latter compound was confirmed on the basis
of elemental analysis and spectral data. The mass
spectrum of 5 revealed a molecular ion peak with m/z 484.
Compound 5 is assumed to proceed via initial Michael
addition of the amino group in compound 3 to an
activated double bond in benzylidenemalononitrile
followed by cyclization to form adduct which did not
aromatize by losing hydrogen cycanide (Scheme 1).
Similar dihydrothieno[2,3-b]pyridine formations have
been reported by us in Ref. [6].
Treatment of S-alkylated derivative 2 with dimethyl-
formamide dimethylacetal (DMF/DMA) in dioxan under
Scheme 1
NH2
N
CN
CN
Ph
Me
N
N
N
S
S
N
H
S
S
5
S
1
PhCH=C(CN)2
C6H5N, reflux
K2CO3
ClCH2COCH3
Me2CO, reflux
NH2
CN
N
S
N
S
Me
S
N
O
N
3
DMF DMA
dioxan
CH2(CN)2
N
S
N
Me
S
S
Me
NMe2
S
S/EtOH,
Et3N, reflux
reflux
N
O
S
N
S
6
2
S
NH2
CN
4

Jul-Aug 2008
Studies with S-Alkylpyrimidine
1059
the basis of its spectral data. Thus, the ir spectrum of the
reaction product revealed NH and nitrile absorptions at
ꢀ
attributed to the 3-H and other resonance at ꢁ 8.46 ppm
attributed to 5-H of pyrazolo[1,5-a]pyrimidine structure
12 (cf. Scheme 2).
max 3439 and 2197 cmꢀ1 respectively (cf. Scheme 2).
Scheme 2
S
N
N
S
N
Me
N
S
N
N
S
NH2
Me
N
S
N
H
O
12
Me
N
9
NH2
N
S
N
EtOH, reflux
Me
N
S, DMF/EtOH
pip, reflux
N
S
O
H
.
Me
CN
pip
/
l
HC
x
N
S
u
OH.
NH2
fl
re
,
N
O
H
11
O
t
E
N
S
N
H
O
N
S
CH2(CN)2, pip.
EtOH, reflux
S
Me
NMe2
8
Me
CN
CN
C
H
N
S
Me
CN
6
2CS
re
NH
NH
2/p
E
t
O
N
S
H
i
p
,
N
S
fl
NH
u
x
S
N
S
O
10
7
The reactivity of enaminone 6 towards nitrogen
On the other hand, treatment of pyrimidine-2(1H)-thione
nucleophile was also investigated. Thus, treatment of 6
derivative 1 with ꢂ-chloroacetic acid in refluxing ethanol
and the presence of potassium hydroxide gave a yellow
crystal of pyrimidin-2'-yl-thioethanoic acid derivative 13 in
good yield. The structure of 13 was established on the basis
of its elemental analysis and spectral data. Thus, the 1H nmr
spectrum of the isolated product exhibited two singlet
signals at ꢁH 4.03 ppm due to methylene protons and the
other one at ꢁH 12.77 ppm attributed to the OH proton. This
signal underwent a facile hydrogen deuterium exchange
upon addition of deuterium oxide. Moreover, the 13C nmr
spectrum of the reaction product characterized by two
signals one at the ꢁC 34.74 corresponding to methylene
carbon and one at ꢁC 171.2 corresponding to an acyl carbon.
The hydroxyl group of 13 was easily transformed into
hydrazide function. Thus, treatment of pyrimidin-2-yl-
thioethanoic acid derivative 13 with hydrazine hydrate in
boiling ethanol gave yellow crystal of pyrimidin-2-yl-
thioacetohydrazide derivative 14 in good yield. The latter
compound proves to be useful key intermediate in the
synthesis of several heterocyclic nuclei.
with hydroxylamine hydrochloride afforded isoxazole
1
derivative 11. The H nmr spectrum revealed a singlet
signal at ꢁH 8.77 corresponding to H-5' of isoxazole [16].
Moreover, the 13C nmr spectrum revealed highest
frequency signals at ꢁC 155 and ꢁC 160 ppm corresponds
to the carbons coupled with proton for isoxazole (C-5')
and pyrimidine (C-6) systems. The formation of 11 is
assumed to proceed via 1,2-addition at carbonyl group in
compound 6 which readily undergoes intramolecular
cyclization into isoxazole derivative 11 via loss of
dimethylamine and a water molecule similar to that which
recently has been reported from our laboratories [ 15].
The results described above prompted us to investigate
the behaviour of compound 6 towards heterocyclic amine
as potential procedures for fused heterocyclic system.
Thus treatment of compound 6 with 3-amino-5-methyl-
1H-pyrazole in refluxing ethanol afforded product of
addition and elimination of both dimethylamine and water
molecules (cf. Scheme 2), which is contrast to recent
report [15]. 1H nmr spectrum revealed two singlet signals
at ꢁ 6.59 ppm which integrates for one proton and
Thus, condensation of acetohydrazide derivative 14 in
situ via one step with benzaldehyde and malononitrile in

1060
F. A. Al-Omran and A. A. El-Khair
Vol 45
standard, ꢂ TMS = 0.00 ppm. Mass spectra were measured on
refluxing ethanol containing pyridine as catalyst, in fact
only a single product was obtained in 75% yield (cf.
Scheme 3). Several structures seemed possible for this
product. Thus, initial formation of adduct 16 (route a)
would lead to pyridazine derivative 18, while the
formation of adduct 19 (route b) would lead to
[1,3,4]triazole[1,5-a]pyridine derivative 21 [17]. The
structure 21 was ruled out on the basis of the elemental
analysis and spectral data. The mass spectrum revealed
m/z = 403 (M+-HCl) corresponding to the molecular
Scheme 3
N
N
KOH, ClCH2COOH
N
SCH2COOH
N
H
S
EtOH, reflux
S
S
13
NH2NH2/EtOH
refluxed
1
N
formula, C20H13N5S2O like that 18.
However, the
N
SCH2CONHNH2
presence of the cyano absorption in the ir spectrum of the
product at ꢀmax 2225 cmꢁ1, indicates that cyano group was
not involved in the reaction which readily excluded the
possibility of 21 (route b). Also the ir spectrum revealed
the higher frequency absorption for a cyclic carbonyl
group stretching band at ꢀmax 1698 cmꢁ1. If the reaction
product is 21 (route b) one would expect the absence of
cyano group and the amide carbonyl group stretching
band absorbed at lower frequency than a cyclic carbonyl
group [5,9]. Moreover, the 1H nmr spectrum revealed the
presence of one D2O exchangeable proton attributed to
the NH function at ꢂ 12.79 ppm and not for NH2. The
formation of pyridazine derivative 18 is assumed to
proceed via initial condensation of benzaldehyde to amino
group in compound 14 yield the intermediate 15. The
latter reacted with malononitrile in situ to give the final
isolated product 18 through the intermediates 16 and 17
(cf. Scheme 3).
S
14
PhCHO, CH2(CN)2
EtOH, C5H5N, reflux, HCl
N
N
SCH2CONHN=CHPh
S
15
b
a
O
NC
C
N
Ph
S
N
NHN=CHPh
N
S
N
N
N
S
C
N
N
S
H
HN
16
19
NH
Ph
NC
Biological Activity. The biological activities of some
of the newly synthesized compounds were screened for
antifungal activity against Aspergillus niger, Penicillium
digitatum and Fusarium while the antibacterial activity
was tested against Bacillus subtilis and Escherichia coli.
Most of the test sample showed bacterial and fungicidal
activity (Table 1).
NH2
N
H
N
S
N
S
N
N
N
N
S
17
O
NH2
N=CHPh
S
20
O
NH2
Ph
NC
N
S
.HCl
N
S
N
EXPERIMENTAL
N
H
N
O
N
N
N
N
S
All melting points are uncorrected. The ir spectra (KBr) were
recorded on a Perkin Elmer 2000 FT-IR spectrophotometer. 1H
nmr and 13C nmr spectra were recorded on a Brucker 400 MHz
spectrometer in DMSO-d6 as solvent using TMS as internal
S
Ph
18
21
Table 1
In vitro antimicrobial and fungicidal activities [a] of some newly synthesized compounds [b-e].
Compound
Bacillus Subtilis
[b]
Escherichia coli
Penicillium digitatum
Aspergillus niger
Fusarium
2
6
-
-
-
-
-
5.0[c]
10.0
-
-
-
7
-
-
-
-
-
10.0
-
5.0
-
10
11
12
13
14
18
-
-
-
-
-
-
-
5.0
-
7.5[d]
-
12.0[e]
-
-
-
10.0
-
-
10.0
10.0[d]
-
-
-
10.0
15.0
15.0[e]
[a] Diameter (in mm) of growth inhibition zones; [b] no activity; [c] little activity; [d] moderate activity; [e] maximum activity.

Jul-Aug 2008
Studies with S-Alkylpyrimidine
1061
GC/MS VS Autospec Q. Microanalyses were performed on a
CHNS-LECO 932 analyzer. Abbreviation: Me2CO = acetone,
1642 (CO) cmꢀ1; 1H nmr (DMSO-d6): ꢁ 2.18 (s, 3H, CH3), 3.14
(s, 3H, NCH3), 3.16 (s, 3H, NCH3), 7.22 (t, 1H, J=3Hz,
thiophene proton), 7.64 (d, 1H, J=3Hz, thiophene proton), 7.83
(d, 1H, J=4 Hz, thiophene proton), 8.00 ppm (d, 1H, J=5 Hz,
H-5', pyrimidine proton), 8.08 (s, 1H, H-4), 8.57 ppm (d, 1H,
J=5 Hz, H-6' pyrimidine-proton); 13C nmr (DMSO-d6): ꢁ 27.4
(CH3), 41.3 (2NCH3), 112.1 (C-5' pyrimidine carbon), 128.5
(C-3), 129.8, 130.1, 130.9 (thiophene carbons), 132.7 (C-4),
142.5 (C-2"), 159.2, 159.5. (C-4' & C-6'), 173.8 (C-2'), 195.6
(CO) ppm; ms: m/z 305 (M+). Anal. Calcd. for C14H15N3S2O
(305.42): C, 55.05; H, 4.95; N, 13.75. Found: C, 54.83; H,
4.79; N, 13.88.
6-Methyl-2-oxo-5-[4'-(2"hienyl)pyrimidin-2'-ylthio]1,2-
dihydropyridine-3-carbonitrile (7). A mixture of 6 (3.05, 10
mmoles) and malononitrile (0.66 g, 10 mmoles) in EtOH (20
mL), containing piperidine was refluxed for 1 hour. The solvent
was evaporated under reduced pressure. The solid product, so
formed, was collected by filtration and recrystallized from EtOH
as yellow crystal, 2.67 g (82 %), mp. 195-197 °C; ir. ꢀ 3425-
3185 (NH), 2208 (CN), 1641 (amide CO) cmꢀ1; 1H nmr (DMSO-
d6): ꢁ 2.39 (s, 3H, CH3), 7.22 (t, 1H, J=4 Hz, thiophene proton),
7.60 (m, 1H, thiophene proton), 7.75 (m, 1H, thiophene proton),
7.92 (d, 1H, J=5 Hz, H-5' pyrimidine proton), 8.00 (br.s, 1H,
NH, D2O exchangeable), 8.22 (s, 1H, H-4), 8.68 ppm (d, 1H,
J=5 Hz, H-6' pyrimidine proton); 13C nmr (DMSO-d6): ꢁ 19.8
(CH3), 101.7 (C-3), 105.2 (C-5), 112.7 (C-5'), 116.9 (CN),
130.1, 130.2, 133.2, 142.0 (thiophene carbons), 156.7 (C-4),
159.2 (C-6), 159.8, 160.0 (C-6' & C-4'), 161.3 (amide CO),
170.7 (C-2') ppm. Anal. Calcd. for C15H10N4OS2 (326.39): C,
55.19; H, 3.08; N, 17.16; S, 19.64. Found: C, 55.01; H, 3.08; N,
17.37; S, 19.46.
6-Methyl-5-[4'-(2"-thienyl)pyrimidin-2'-ylthio]-2-thioxo-
1,2-dihydropyridine-3-carbonitrile (10). A mixture of 6 (3.05
g, 10 mmoles) and cyanothioacetamide (1.00 g, 10 mmoles) in
EtOH (20 mL) containing piperidine was refluxed for 1 hour.
The solvent was evaporated under reduced pressure. The solid
product, so formed, was collected by filtration and recrystallized
from EtOH as green crystal, 2.59 g (76%), mp. 240-242 °C; ir.
ꢀ 3439-3365 (NH), 2197 (CN) cmꢀ1; 1H nmr (DMSO-d6): ꢁ 2.45
(s, 3H, CH3), 7.22 (t, 1H, J=4 Hz, thiophene proton), 7.75 (m,
1H, thiophene proton), 7.88 (m, 1H, thiophene proton), 8.02 (d,
1H, J=5 Hz, H-5' pyrimidine proton), 8.26 (s, 1H, H-4), 8.68 (d,
1H, J=5 Hz, H-6' pyrimidine proton), 14.60 ppm (br.s, 1H, NH,
D2O exchangeable); 13C nmr (DMSO-d6): ꢁ 19.3 (CH3), 112.7
(C-5'), 113.3 (C-3), 115.4 (C-5), 117.2 (CN), 129.9, 130.5,
133.0, 141.8 (thiophene carbons), 151.8 (C-4), 159.6, 159.9 (C-
6' & C-4'), 160.2 (C-2), 169.7 (C-6), 179.6 (C-2') ppm. Anal.
Calcd. for C15H10N4S3 (342.46): C, 52.60; H, 2.94; N, 16.36.
Found: C, 52.47; H, 3.14; N, 16.12.
2-(3'-Methylisoxazo-4'-ylthio)-4-(2"-thienyl)pyrimidine (11).
A mixture of 6 (3.05 g , 10 mmoles) and hydroxylamine
hydrochloride (0.69 g, 10 mmoles) in EtOH (20 mL) was
refluxed for 1 hour. The reaction mixture was left to cool at
room temperature. The solid product, so formed, was collected
by filtration and recrystallized from EtOH as brown crystal,
1.89 g (69 %); mp. 80-82°C; 1H nmr (DMSO-d6): ꢁ 2.18 (s, 3H,
CH3), 7.24 (t, 1H, J=4Hz, thiophene proton), 7.75 (m, 1H,
thiophene proton), 7.86 (m, 1H, thiophene proton), 8.09 (d, 1H,
J=5 Hz, H-5 pyrimidine proton), 8.63 (d, 1H, J=5 Hz, H-6
pyrimidine proton), 8.77 ppm (s, 1H, H-5'); 13C nmr (DMSO-d6):
ꢁ 19.6 (CH3), 102.0 (C-4'), 112.7 (C-5), 129.9, 130.6, 133.1,
141.7 (thiophene carbons), 154.5 (C-3'), 155.4 (C-5'), 159.6,
EtOH
= ethanol, Et3N = triethylamine, DMF = N,N-
dimethylformamide, DMSO-d6 = dimethyl-d6-sulfoxide, TMS =
tetramethylsilane, DMF/DMA
dimethylacetal.
=
N,N-dimethylformamide
1-[4'-(2"-Thienyl)pyrimidin-2'-ylthio]propan-2-one (2). A
mixture of (1.94 g, 10 mmoles) potassium carbonate
1
anhydrous (1.38 g, 10 mmoles) and chloroacetone (0.79 g, 10
mmoles) in Me2CO (20 mL) was refluxed for 2 hours. The
solvent was then evaporated under reduced pressure. The solid
product, so formed, was collected by filtration and recrystallized
from EtOH as light brown crystal, 2.0 g (73%),mp. 80-82 °C; ir.
1
ꢀ 1716 (CO) cmꢀ1; H nmr (DMSO-d6): ꢁ 2.34 (s, 3H, CH3),
4.21 (s, 2H, CH2), 7.23 (t, 1H, J=3Hz, thiophene proton), 7.65
(d, 1H, J=3Hz, thiophene proton), 7.84 (d, 1H, J=4 Hz,
thiophene proton), 8.03 (d, 1H, J=5Hz, H-5' pyrimidine proton),
8.56 ppm (d, 1H, J=5 Hz, H-6' pyrimidine proton); 13C nmr
(DMSO-d6): ꢁ 20.0 (CH3), 42.0 (CH2), 112.1 (C-5'), 130.0,
130.5, 132.9 (thiophene carbons), 140.1 (C-2"), 159.1 (C-4'),
159.6 (C-6'), 171.1 (C-2'), 203.0 (CO) ppm; ms: m/z 250 (M+).
Anal. Calcd. for C11H10N2OS2 (250.21): C, 52.80; H, 4.03; N,
11.20; S, 25.62. Found: C, 52.89; H, 4.02; N, 11.24; S, 25.68.
2-Amino-4-methyl-5-[4'-(2"-thienyl)pyrimidin-2'-ylthio]-
thiophene-3-carbonitrile (3). A mixture of 2 (2.50 g, 10
mmoles) malononitrile (0.66 g, 10 mmoles) and elemental sulfur
(0.32 g, 10 mmoles) in EtOH (20 mL) containing Et3N was
refluxed for 3 hours. The reaction mixture was left to cool at
room temperature, then poured onto ice cold water. The solid
product, so formed, was collected by filtration and recrystallized
from a EtOH as brown crystal, 2.0 g (79%),mp. 130-132 °C; ir.
ꢀ 3431-3329 NH2, 2201 (CN) cmꢀ1; 1H nmr (DMSO-d6): ꢁ 2.12
(s, 3H, CH3), 4.37 (br.s, 2H, NH2, D2O exchangeable), 7.17 (m,
1H, thiophene proton), 7.55 (m, 1H, thiophene proton), 7.71 (m,
1H, thiophene proton), 7.89 (d, 1H, J=5 Hz, H-5' pyrimidine
proton), 8.47 ppm (d, 1H, J=5 Hz, H-6' pyrimidine proton); ms:
m/z 330 (M+). Anal. Calcd. for C14H10N4S3 (330.45): C, 50.91;
H, 3.05; N, 16.97. Found: C, 51.02; H, 3.04; N, 17.03.
4-Amino-3-methyl-6-phenyl-2-[4'-(2"-thienyl)pyrimidin-
2'-ylthio]thieno[2,3-b]pyridine-5,5-(4H)dicarbonitrile (5). A
mixture of 3 (3.30 g, 10 mmoles) and benzylidinemalononitrile
(1.54 g, 10 mmoles) in pyridine (20 mL) was refluxed for 3
hours. The reaction was poured onto ice-cold water and
acidified with 10% HCl. The solid product, so formed, was
collected by filtration and recrystallized from EtOH as brown
crystal, 3.33 g (69 %), mp. 220-222 °C; ir. ꢀ 3435 (NH2), 2204
1
(2CN) cmꢀ1; H nmr (DMSO-d6): ꢁ 2.11 (s, 3H, CH3), 4.11 (s,
1H, H-4), 7.22-8.66 (m, 12H, aromatic protons & NH2); 13C nmr
(DMSO-d6): ꢁ 15.1 (CH3), 29.2 (C-5), 37.7 (C-4), 113.5 (C-5'),
114.3 & 115.2 (2CN), 119.6 (C-2), 130.2, 130.6, 130.7, 131.5,
132.8, 133.4, 135.5 (phenyl & thiophene carbons), 141.8, 142.8
(C-3 & C-3a), 142.0 (C-2”), 154.0 (C-7a), 159.3, 159.8 (C-4' &
C-6'), 162.6 (C-6), 171.6 (C-2') ppm, ms: m/z 484 (M+). Anal.
Calcd. for C24H16N6S3 (484.17): C, 59.48; H, 3.32; N, 17.34.
Found: C, 59.85; H, 3.35; N, 17.46.
4-(N,N-Dimethylamino)-3-[4'-(2"-thienyl)pyrimidin-2'-yl-
thio]-3-buten-2-one (6). A solution of 2 (2.50 g, 10 mmoles)
in dioxan (20 mL) was treated with DMF DMA (1.33 g, 10
mmoles) and refluxed for 5 hours. The solvent was then
evaporated under reduced pressure. The solid product, so
formed, was collected by filtration and recrystallized from
EtOH as yellow crystal, 2.62 g (86%),mp. 105-107 °C; ir: ꢀ

1062
F. A. Al-Omran and A. A. El-Khair
Vol 45
159.9 (C-4
&
C-6); 173.8 (C-2) ppm. Anal. Calcd. for
crystal, 3.29 g (75 %), mp. 173-174 °C; ir. ꢁ 3408 (NH), 2225
(CN), 1698 (CO) cmꢀ1; 1H nmr (DMSO-d6): ꢀ 3.98 (s, 2H, CH2),
7.22 (t, 1H, J=4 Hz, thiophene proton), 7.59-7.66 (m, 5H, phenyl
protons), 7.67 (m, 1H, thiophene proton), 7.85 (m, 1H,
thiophene proton), 8.05 (d, 1H, J=5 Hz, H-5' pyrimidine proton),
8.58 (d, 1H, J=5 Hz, H-6' pyrimidine proton), 12.79 ppm (br.s,
1H, NH, D2O exchangeable); 13C nmr (DMSO-d6): ꢀ 34.2 (CH2),
82.6 (C-5), 112.1 (C-5'), 115.2 (CN), 136.6 (C-3), 130.0, 130.5,
130.6, 131.5, 132.3, 132.9, 135.4, 142.1 (phenyl & thiophene
carbons), 159.2, 159.5 (C-4' & C-6'), 162.6 (C-6), 171.0 (C-2'),
171.2 (CO) ppm; ms:m/z 403 (M+-HCl). Anal. Calcd. for
C20H14N5S2OCl (439.94): C, 54.60; H, 3.20; N, 15.91. Found: C,
54.75; H, 3.34; N, 15.80.
C12H9N3S2O (275.37): C, 52.34; H, 3.29; N, 15.26. Found: C,
52.37; H, 3.37; N, 15.03.
2,7-Dimethyl-6-[4'-(2"-thienyl)pyrimidin-2'-ylthio]pyra-
zolo[1,5-a]pyrimidine (12). A solution of 6 (3.05 g, 10 mmoles)
in EtOH (20 mL) was treated with 3-amino-5-methyl-1H-
pyrazole (0.97 g, 10 mmoles). The reaction mixture was
refluxed for 3 hours and left to cool at room temperature. The
solid product, so formed, was collected by filtration and
recrystallized from EtOH as brown crystal, 2.43 g (72 %), mp.
1
143-145 °C; H nmr (DMSO-d6): ꢀ 2.46 (s, 3H, CH3), 2.79 (s,
3H, CH3), 6.59 (s, 1H, H-3), 7.15 (m, 1H, thiophene proton),
7.65 (m, 1H, thiophene proton), 7.75 (m, 1H, thiophene proton),
7.93 (d, 1H, J=4 Hz, H-5' pyrimidine proton), 8.46 (s, 1H, H-5),
8.50 ppm (d, 1H, J=4 Hz, H-6' pyrimidine proton); 13C nmr
(DMSO-d6): 15.4 (CH3), 16.2 (CH3), 97.5 (C-3), 112.6 (C-5'),
129.8, 130.4, 132.9, 141.7 (thiophene carbons), 149.6 (C-2),
149.2 (C-6), 151.6 (C-5), 154.7 (C-3a), 156.1 (C-7), 159.5,
159.8 (C-4' & C-6'), 170.5 (C-2') ppm. Anal. Calcd for
C16H13N5S2 (339.43): C, 56.61; H, 3.86; N, 20.63. Found: C,
56.54; H, 3.75; N, 20.68.
2-[4'-(2"-Thienyl)pyrimidin-2'-ylthio]ethanoic acid (13). A
solution of 1 (1.94 g, 10 mmoles) and potassium hydroxide (0.56
g, 10 mmoles) in EtOH (20 mL) was treated with chloroacetic
acid (0.94 g, 10 mmoles). The reaction mixture was refluxed
for 2 hours and left to cool at room temperature. The solid
product, so formed, was collected by filtration and recrystallized
from EtOH as yellow crystal, 1.78 g (71 %), mp. 201-203 °C;
ir.ꢁ 3500-3360 (OH), 1698 (CO) cmꢀ1; 1H nmr (DMSO-d6): ꢀ
4.03 (s, 2H, CH2), 7.25 (m, 1H, thiophene proton), 7.67 (m, 1H,
thiophene proton), 7.82 (m, 1H, thiophene proton), 7.89 (d, 1H,
J=4 Hz, H-5' pyrimidine proton), 8.60 (d, 1H, J=4 Hz, H-6'
pyrimidine proton), 12.77 ppm (br.s, 1H, OH, D2O
exchangeable); 13C nmr (DMSO-d6): ꢀ 34.74 (CH2), 112.1 (C-
5'), 130.3, 130.6, 133.0 (thiophene carbons), 142.1 (C-2"),
159.2,159.6 (C-4' & C-6'), 171.0 (C-2'), 171.2 (CO) ppm. Anal.
Calcd for C10H8N2S2O2 (252.18): C, 47.62; H, 3.20; N, 11.11.
Found: C, 47.54; H, 3.33; N, 11.15.
2-[4'-(2"-Thienyl)pyrimidin-2'-ylthio]acetohydrazide (14).
A solution of 13 (2.52 g, 10 mmoles) in EtOH (20 mL) was
treated with hydrazine hydrate (0.50 g, 10 mmoles). The
reaction mixture was refluxed for 1 hour and left to cool at room
temperature. The solid product, so formed, was collected by
filtration and recrystallized from EtOH as yellow crystal, 1.99 g
(75 %), mp. 201-212 °C; ir.ꢁ 3195-3319 (NH & NH2), 1618
(amide CO) cmꢀ1; 1H nmr (DMSO-d6): ꢀ 1.59 (br.s, 2H, NH2,
D2O exchangeable), 3.87 (s, 2H, CH2), 7.23 (t, 1H, J=4 Hz,
thiophene proton), 7.28 (br.s, 1H, NH, D2O exchangeable), 7.49
(m, 1H, thiophene proton), 7.64 (m, 1H, thiophene proton), 7.86
(d, 1H, J=5 Hz, H-5' pyrimidine proton), 8.51 ppm (d, 1H, J=5
Hz, H-6' pyrimidine proton). Anal. Calcd for C10H10N4S2O
(266.21): C, 45.11; H, 3.78; N, 21.04. Found: C, 45.11; H, 3.92;
N, 20.99.
Biological Testing. The newly synthesized compounds were
tested against the specified microorganism, using 400 μg/mL
(w/v) solutions in sterile dimethyl-d6-sulfoxide (DMSO).
A
solution of the tested compound (.01 mL) was poured aseptically
in a well of 6 mm diameter made by a Cork borer in the nutrient
agar medium for bacterial test and Sabourand agar for fungal
test. After placing the same volume in wells of all tested
microorganism, nutrient agar plates were incubated at 37 °C for
24 hours and Sabourand dextrose agar plates were incubated at
25 °C for 48 hours. The diameter of zones inhibition was
measured in millimeters and the results are shown in Table 1.
The least concentration, which showed inhibitory effect on any
specific microorganism, was considered as the minimum
inhibitory concentration (MIC) which was determined using
streptomycin (50 μg/mL) as the references.
Acknowledgement. This work was financed by the
University of Kuwait research grant SC07/04. We are grateful
to the Faculty of Science, Chemistry Department, SAF facility
for the spectral and analytical data (Project GS 01/01 & GS
03/01). We are grateful to Dr. S.A. Abdel-Gahny for biological
activity tests.
REFERENCES
* Corresponding Author: E-mail: falomran@kuc01.kuniv.edu.kw or
chesc@kuc01.kuniv.edu.kw
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