A facile and efficient synthesis of polynuclear heterocycles: Azolothienopyrimidines and thienothiazolopyrimidines with antimicrobial activity

Article abstract of DOI:10.1080/10426500701370342

The research group I am a member of is interested in the preparation of thieno[2, 3-d]pyrimidine fused with different heterocycles compounds with potential biological activity. 2-Arylmethylene derivatives 4a-g were prepared in one step by reacting 2-thiox

Full text of DOI:10.1080/10426500701370342

This article was downloaded by: [McGill University Library]
On: 07 December 2012, At: 03:09
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
A Facile and Efficient Synthesis
of Polynuclear Heterocycles:
Azolothienopyrimidines and
Thienothiazolopyrimidines with
Antimicrobial Activity
H. A. R. Hussein a
a Department of Photochemistry (Heterocyclic Unit),
National Research Centre, Dokki, Cairo, Egypt
Version of record first published: 16 Jul 2007.
To cite this article: H. A. R. Hussein (2007): A Facile and Efficient Synthesis of
Polynuclear Heterocycles: Azolothienopyrimidines and Thienothiazolopyrimidines
with Antimicrobial Activity, Phosphorus, Sulfur, and Silicon and the Related Elements,
182:9, 2069-2085
To link to this article: http://dx.doi.org/10.1080/10426500701370342
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be

independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 182:2069–2085, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701370342
A Facile and Efficient Synthesis of Polynuclear
Heterocycles: Azolothienopyrimidines and
Thienothiazolopyrimidines with Antimicrobial Activity
H. A. R. Hussein
Department of Photochemistry (Heterocyclic Unit),
National Research Centre, Dokki, Cairo, Egypt
The research group I am a member of is interested in the preparation of thieno[2,
3-d]pyrimidine fused with different heterocycles compounds with potential biolog-
ical activity. 2-Arylmethylene derivatives 4a–g were prepared in one step by re-
acting 2-thioxothienopyrimidine derivatives 3a,b with chloroacetic acid and the
proper aldehyde. The ester 3a and the acid 3b were alkylated at different reac-
tion conditions to produce the 2-alkylthio derivatives 5a–d. Further alkylation of
5c produced the N-3 alkylated product 6. Compounds 5b,d were cyclized in boil-
ing acetic anhydride/pyridine to produce the thiazolothienopyrimidinone deriva-
tives 7a,b, respectively. Compounds 5a,c reacted with hydrazine hydrate to give
2-hydrazinothienopyrimidines 8a,b which could be used as precursors for tria-
zolothienopyrimidines 9a,b and pyrazolylthienopyrimidines 10a–c,13. The pur-
pose: Synthesis of thienopyrimidine derivatives which are highly biological active
toward bacteria and fungi.
Keywords aliphatic acids; antibacterial; antifungal; biological activity; mass spectra;
NMR spectra; polynuclear; thienothiazolopyrimidines
INTRODUCTION
Fused pyrimidines continue to attract considerable attention of re-
searchers in different countries because of their great practical use-
fulness, primarily, due to a very wide spectrum of their biological
activities.1–5 The pyrimidine ring is fused to various heterocycles to
form compound with highly biological activities. Thienopyrimidine oc-
cupy a special position among these compounds. I hereby report the
syntheses of new polynuclear heterocyclic thienopyrimidines, start-
ing with 2-thioxo-[4,5]thieno[2,3-d]pyrimidin-4-one derivatives 3a,b.
Received February 4, 2006; accepted March 14, 2007.
Address correspondence to H. A. R. Hussein, Department of Photochemistry, Hetero-
cyclic Unit, National Research Centre, Dokki, Cairo, Egypt. E-mail: hodarf@hotmail.com
2069

2070
H. A. R. Hussein
Thus heating under reflux 3,5-diethyl-2-amino-4-methyl-thiophene-
3,5-dicarboxylate (1), prepared according to Karl Gewald method.6
Compound 1 was refluxed with potassium thiocyanate in dry dioxane
in the presence of hydrochloric acid to give N-[3,5-diethoxycarbonyl-4-
methylthien-2-yl]thiourea (2). Cyclization of compound 2 depends on
the reaction conditions. Thus, it cyclized in acetic acid in the presence
of sodium acetate to yield compound 3a. The IR spectrum of 3a (KBr)
cm−1: 3255(NH), 3107 (NH); 1691 (CO) and 1663 (CO); 1H-NMR of
3a (DMSO-d6), as an example, showed signals at δ1.30 ppm (t, 3H,
CH3), 2.75 (s, 3H,CH3), 4.35 (q, 2H, CH2), 12.60 (br s, 1H, NH, D2O
exchangeable) and 13.55 (br s, 1H,NH, D2O exchangeable), MS (m/z):
270.0 (M+) 100%.
On the other hand when compound 2 was treated with 10% NaOH fol-
lowed by acidification, it underwent cyclization and hydrolysis forming
the free acid 3b, in good yield. Its1H-NMR spectrum showed no signal
corresponding to ester and a signal of (OH) appeared, Experimental.
On heating under reflux a mixture of compound 3a,b, chloroacetic
acid and aromatic aldehyde in acetic acid and acetic anhydride in pres-
ence of anhydrous sodium acetate, it gave 4a–g in good yield. Beside
the correct values in elemental analyses, the spectral data of 4a–g are
in agreement with the assigned structure, Experimental.
Methyl iodide and 3-chloropentane-2,4-dione were used to alky-
late each of the ester 3a in potassium carbonate solution and the

Azolothienopyrimidines and Thienothiazolopyrimidines
2071
acid 3b in ethanolic potassium hydroxide solution. The S-alkylation
products could be formed as the 2-alkylthio-5-methyl-3H-thieno[2,3-
d]pyrimidine-6-carboxylate (5a,b) and 6-carboxylic acid analogues
(5c,d), respectively. The IR spectra of 5a–d (KBr) cm−1 showed: (NH)
around 3150 and (2CO) around 1720, 1660; 1H-NMR of 5a (DMSO-d6),
as an example, showed signals at δ1.30 ppm (t, 3H, CH3), 2.45 (s 3H,
CH3), 2.80 (s, 3H, CH3), 4.30 (q, 2H, CH2) and 12.90 (br s, 1H, NH, D2O
exchangeable); MS (m/z): 284.0 (M+) 100%.
The 2-alkylthio derivative 5c underwent further alkylation7 on treat-
ment with ethyl iodide in aqueous ethanolic potassium hydroxide solu-
tion to produce the N-3 alkylated product 6 in good yield (Scheme 1).
Heating 5b,d in a mixture of acetic anhydride/pyridine, led to forma-
tion of the cyclic product 7a,b. Beside the correct values in elemental
analyses, the spectral data of 6 and 7a,b are in agreement with the
assigned structure, see experimental.
When 5a–c reacted with hydrazine hydrate it gave the 2-hydrazino
derivatives 8a,b. The IR spectra of 8a,b (KBr) cm−1 showed: [(NH2),
1
(NH)] around 3270; 3170 and (2CO) around 1690, 1660; H-NMR of
8b (DMSO-d6), as an example, showed signals at δ2.75 ppm (s, 3H,
CH3), 5.00 (br, 2H, NH2, D2O exchangeable), 8.20 (br s, 1H, NH, D2O
exchange-able) and 12.90 (s, 1H, OH, D2O exchangeable); MS (m/z):
240(M+) 43%; 196 (M+-COOH)100%, (Scheme 1).
SCHEME 1
The 2-hydrazinopyrimidine derivative 8b used to prepare
some new azolothienopyrimidines and pyrazolylthienopyrimidine

2072
H. A. R. Hussein
derivatives. Thus, heating under reflux, the 2-hydrazino 8b with either
formic acid or acetic acid yielded 5H-thieno[2,3-d][1,2,4]triazolo[4,3-
a]pyrimidin-5-one derivatives 9a,b. The IR spectra of 9a,b (KBr) cm−1
showed: (OH) around 3430, (NH) around 3130 and (2CO)around1680,
1650; 1H-NMR of 9a (DMSO-d6), as an example, showed signals
at δg.45 ppm (s, 3H, CH3), 6.75 (s, 1H, CH), 9.10 (s, 1H, NH, D2O
exchangeable) and 11.90 (1H, OH, D2O exchangeable); MS (m/z):
250(M+) 100%.
When equimolar amounts of 8b and pentane-2,4-dione, 3-chloro-
pentane-2,4-dione or triflouro-pentane-2,4-dione were heated under
reflux in absolute ethanol, the 2-pyrazolylthieno[2,3-d]pyrimidinones
10a–c were obtained in good yield.
Also, compound 8b gave the arylhydrazone derivatives 11a,b, when
it was treated with the appropriate aldehyde in boiling dioxane in pres-
ence of catalytic amounts of piperidine. Trials to cyclize 11a,b under
different conditions had failed.
Heating under reflux compound 8b with ethyl acetoacetate in abso-
lute ethanol afforded the hydrazone derivative 12, which could be cy-
clized by heating in ethanolic sodium ethoxide solution to give 13. Also,
compound 13 can be achieved directly from compound 8b by heating
with ethyl acetoacetate in ethanolic sodium ethoxide solution.
1
Beside the correct values in elemental analyses, the IR, H-NMR
and Mass spectra of 10a–c, 11a,b and 13 are in agreement with the
assigned structure, see experimental, (Scheme 2).
BIOLOGICAL SCREENING
Measurement of Antimicrobial Activity Using Diffusion
Disc Method
The prepared compounds were tested against one strain of gram +ve
bacteria (staphylococcus aureus G+), gram -ve bacteria (Pseudomon
as aeruginosa G), Fungi (Saccharomyces cereviseae) and Fungi (Can-
dida albicans). Whatman No. 1 filter paper disk of 5 mm diameter
were sterilized by autoclaving for 15 min at 121◦C. The sterile disks
were impregnated with different compounds (600 µg/disk) Agar plates
were surface inoculated uniformly from the broth culture of the tested
microorganism.
The impregnated discs were placed on the medium suitably spaced
apart, and the plates were incubated at 5◦C for 1 h to permit good
diffuse-ion and then transferred to an incubator at 37◦C for 24 h for
bacteria, at 28◦C for 72 h for fungi.

Azolothienopyrimidines and Thienothiazolopyrimidines
2073
SCHEME 2
After inoculation, the inhibition zones caused by the various com-
pounds on the microorganism were examinant. The diameter of the
clear zone of inhibition surrounding the sample is taken as a mea-
sure of the inhibitory power of the sample against the particular test
organism.8,9 The results of the preliminary screening test are listed in
(Table I).
The antibacterial and antifungal activity of compounds 1, 2, 4c, 4f,
4g, 6, 7a, 7b and 12 were tested. From the data obtained in Table I, it is
clear that all above compounds were found to be highly active against
Candida albicans (fungus), Saccharomyces cereviseae, staphylococcus
aureus G+ and Pseudomonas aeruginosa G .
–
EXPERIMENTAL
All melting points are uncorrected and were taken in open capillaries on
a Gallen Kamp Apparatus. Microanalyses were carried out at the Mi-
croanalytical units, National Research Center and Faculty of Science,
Cairo University. IR spectra were carried out at a FT/IR-300 E Jasco

2074
H. A. R. Hussein
TABLE I Data of Antimicrobial Activity Toward Some Products
Inhibition zone diameter ( mm / mg sample )
Pseudomonas
aerubinosa
( G−)
Staphylococcos
aureus
Saccharomyces
cereviseae
Candida
albicans
( Fungus )
Sample
Control
1
2
4c
4f
4g
6
7a
7b
12
( G+)
(Fungus )
0.0
14
12
13
14
15
13
14
15
14
0.0
12
13
13
15
15
13
13
14
14
0.0
13
11
12
14
15
12
13
15
13
0.0
14
12
12
14
15
14
13
15
13
G : Gram reaction; Solvent : Chloroform and DMSO.
using KBr discs. 1H-NMR spectra were measured in DMSO or CDCl3,
using JEOL-JNM-Ex270 NMR spectrometer. Signals were measured
with reference to TMS as an internal standard. The Mass spectra were
recorded on Finnigan SSQ 7000 spectrometer. All solid compounds were
recrystallized to produce constant melting points. All the physical data
is in Table I.
3,5-Diethyl-2-amino-4-methyl-thiophene-3,5-dicarboxylate (1)
Compound 1 was prepared according to Karl Gewald method.6
N-[3,5-Diethoxycarbonyl-4-methylthien-2-yl]thiourea (2)
A mixture of 1 (2.57g, 0.01 mole), potassium thiocyanate (0.97 g,
0.01 mole), and concentrated hydrochloric acid (30 ml) was refluxed
in dioxane (30 ml) for five hours (the reaction was followed by TLC).
The reaction mixture was cooled and poured into water. The deposited
precipitate was filtered-off and recrystallized from dioxane to produce
2 as yellow crystals; IR spectrum (KBr) cm−1: 3387, 3312 (NH2), 3216
(NH), 1681 (CO) and 1648 (CO); 1H-NMR (DMSO-d6) δ ppm: 1.35 (m,
6H, 2CH3), 2.75 (s, 3H, CH3), 4.35 (m, 4H, 2CH2), 8.85 (br s, 2H, NH2,
D2O exchangeable), and 11.75 (s, 1H,NH, D2O exchangeable); MS (m/z):
316 (M+) 100%.
Ethyl-5-methyl-4-oxo-2-thioxo-1H,
3H-thieno[2,3-d]pyrimidin-6-carboxylate (3a)
Compound 3a was obtained by heating compound 2 (3.16g, 0.01 mole)
under reflux in glacial acetic acid and anhydrous sodium acetate. Collect

Azolothienopyrimidines and Thienothiazolopyrimidines
2075
the formed precipitate by filtration, wash with water, and recrystallize
from dioxane to produce a colorless powder 3a; IR spectrum(KBr) cm−1
:
3255(NH), 3107 (NH); 1691 (CO) and 1663 (CO); 1H-NMR (DMSO-
d6) δ ppm: 1.30 (t, 3H, CH3), 2.75 (s, 3H,CH3), 4.35 (q, 2H, CH2), 12.60
(br s, 1H, NH, D2O exchangeable), and 13.55 (br s, 1H,NH, D2O ex-
changeable); MS (m/z): 270.0 (M+) 100%.
5-Methyl-4-oxo-2-thioxo-1H,
3H-thieno[2,3-d]pyrimidin-6-carboxylic acid (3b)
Compound 3b was obtained by boiling compound 2 (3.16g, 0.01 mole)
in 10% NaOH solution [prepared by 10 g NaOH in 100ml water]. Allow
to cool, acidify with conc. HCl, and collect the formed precipitate. Wash
with water and recrystallize from dioxane to produce a colorless powder
3b; IR spectrum(KBr) cm−1: 3446(OH), 3128 (NH); 1713 (CO) and 1683
1
(CO); H-NMR (DMSO-d6) δ ppm: 2.70 (s, 3H,CH3) and 12.50 (br s,
1H,OH, D2O exchangeable); MS (m/z): 242.0 (M+) 100%.
General Method for Preparation 4a–g
A mixture of compound 3a or 3b (2.70 g or 2.42 g, 0.01 mole), chloroacetic
acid (0.95 g, 0.01 mole), appropriate aromatic aldehyde (0.01 mole),
and anhydrous sodium acetate (0.02 mole) was refluxed in (30 ml) of
glacial acetic acid and (15 ml) of acetic anhydride for 5 h. The reaction
mixture was cooled and poured into water. The deposited precipitate
was filtered-off, and recrystallized from suitable solvent to produce 4a–
g.
Ethyl-3,5-Dioxo-6-methyl-2-(phenylmethylene)-thiazolo[3,2-
a]thieno[2,3-d]pyrimi-dine-7-carboxylate (4a)
Compound 4a was obtained by reaction of 3a (2.70 g, 0.01 mole) and
benzaldehyde (1.06 g, 0.01 mole). The product was recrystallized from
dioxane to produce 4a as pale yellow crystals; IR spectrum (KBr) cm−1
:
1770 (CO), 1720 (CO) and 1680 (CO); 1H-NMR (DMSO-d6) δ ppm:
1.35 (t, 3H, CH3), 2.85 (s, 3H, CH3), 4.35 (q, 2H, CH2), 7.50–7.70 (m,
5H, phenyl protons) and 8.10 (s, 1H, CH); MS (m/z): 398 (M+) 100%.
Ethyl-3,5-Dioxo-6-methyl-2-(4-methoxyphenylmethylene)-
thiazolo[3,2-a]thieno[2,3-d]pyrimidine-7-carboxylate (4b)
Compound 4b was obtained by reaction of 3a (2.70 g, 0.01 mole) and
4-methoxybenzaldehyde (1.36 g, 0.01 mole). The product was recrystal-
lized from dioxane to produce 4b orange crystals; IR spectrum (KBr)
cm−1: 1760 (CO), 1715 (CO), and 1675 (CO); MS (m/z): 428 (M+) 100%.

2076
H. A. R. Hussein
Ethyl-3,5-Dioxo-6-methyl-2-(4-chlorophenylmethylene)-
thiazolo[3,2-a]thieno[2,3-d]pyrimidine-7-carboxylate (4c)
Compound 4c was obtained by reaction of 3a (2.70 g, 0.01 mole) and
4-chlorobenz-aldehyde (1.40 g, 0.01 mole). The product was recrystal-
lized from dioxane to produce 4c as yellow crystals; IR spectrum (KBr)
1
cm−1: 1765 (CO), 1715 (CO) and 1685 (CO); H-NMR (DMSO-d6)
δ
ppm: 1.40 (t, 3H, CH3), 2.80 (s, 3H, CH3), 4.25 (q, 2H, CH2), 7.75 (d,
2H, aromatic protons), 7.85 (d, 2H, aromatic protons), and 8.00 (s, 1H,
ethylenic proton); MS (m/z): 432, 434[M+, (100%, 53.%)].
3,5-Dioxo-6-methyl-2-(phenylmethylene)-thiazolo[3,2-
a]thieno[2,3-d]pyrimidine-7-carboxylic Acid (4d)
Compound 4d was obtained by reaction of 3b (2.42 g, 0.01 mole) and
benzaldehyde (1.06 g, 0.01 mole). The product was recrystallized from
dimethylformamide to produce 4d as pale yellow crystals; IR spectrum
(KBr) cm−1: 3566(OH), 1765 (CO), 1715 (CO) and 1672 (CO); 1H-NMR
(DMSO-d6) δ ppm: 2.80 (s, 3H, CH3), 7.50–7.65 (m, 5H, phenyl pro-
tons), 8.10 (s, 1H, CH), and 12.50 (s, 1H, OH, D2O exchangeable); MS
(m/z): 370 (M+) 100%.
3,5-Dioxo-6-methyl-2-(4-methoxyphenylmethylene)-
thiazolo[3,2-a]thieno[2,3-d]pyri-midine-7-carboxylic Acid (4e)
Compound 4e was obtained by reaction of 3b (2.42 g, 0.01 mole)
and 4-methoxybenz-aldehyde (1.36 g, 0.01 mole). The product was re-
crystallized from dimethylformamide to produce 4e orange crystals; IR
spectrum (KBr) cm−1: 3567(OH), 1762 (CO), 1715 (CO) and 1673 (CO);
MS (m/z): 400(M+) 100%.
3,5-Dioxo-6-methyl-2-(4-chlorophenylmethylene)-thiazolo[3,2-
a]thieno[2,3-d]pyrim-idine-7-carboxylic Acid (4f)
Compound 4f was obtained by reaction of 3b (2.42 g, 0.01 mole) and 4-
chlorobenz-aldehyde (1.40 g, 0.01 mole). The product was recrystallized
from dimethylformamide to produce 4f as yellow crystals; IR spectrum
(KBr) cm−1: 3550(OH), 1766 (CO), 1710 (CO) and 1676 (CO); 1H-NMR
(DMSO-d6) δ ppm: 2.85 (s, 3H, CH3), 7.00 (d, 2H, aromatic protons),
7.30 (d, 2H, aromatic protons), 8.00 (s, 1H, ethylenic proton) and 11.85
(s, 1H, OH, D2O exchangeable); MS (m/z): 404, 50, 406.50[M+, (84%,
39.%)].

Azolothienopyrimidines and Thienothiazolopyrimidines
2077
3,5-Dioxo-6-methyl-2-(4-triflurophenylmethylene)-
thiazolo[3,2-a]thieno[2,3-d]pyri-midine-7-carboxylic Acid (4g)
Compound 4g was obtained by reaction of 3b (2.42 g, 0.01 mole) and
4-trifluorobenzaldehyde (1.86 g, 0.01 mole). The product was recrys-
tallized from dimethylformamide to produce 4f as yellow crystals; IR
spectrum (KBr) cm−1: 3450(OH), 1760 (CO), 1700 (CO) and 1670 (CO);
1H-NMR (DMSO-d6) δ ppm: 2.85 (s, 3H, CH3), 7.60 (d, 2H, aromatic
protons), 7.70 (d, 2H, aromatic protons), 8.05 (s, 1H, ethylenic proton),
and 12.00 (s, 1H, OH, D2O exchangeable); MS (m/z): 438%.
General Method for Preparation 5a,b
A mixture of 3a (2.70 g, 0.01 mole) and potassium carbonate (1.38 g,
0.01 mole) in pure acetone was heated for 30 min, then allowed to cool
to room temperature, and the proper halo compound (0.013 mole) was
added. The mixture was heated under reflux for 5 h, then cooled and
poured into water. The solid product was filtered-off and recrystallized
from appropriate solvent to produce 5a,b.
Ethyl-5-Methyl-2-methylthio-3H-thieno[2,3-d]pyrimidine-6-
carboxylate (5a)
Compound 5a was obtained by reaction of 3a and methyl iodide
(1.72 g, 0.013 moles). The compound was recrystallized from dioxane to
produce 5a as colorless crystals; IR spectrum (KBr) cm−1: 3157 (NH);
1
1717 (CO) and 1667 (CO); H-NMR (DMSO-d6) δ ppm: 1.30 (t, 3H,
CH3), 2.45 (s 3H,CH3), 2.80 (s, 3H, CH3), 4.30 (q, 2H, CH2) and 12.90
(br s, 1H, NH, D2O exchangeable); MS (m/z): 284.0 (M+) 100%.
Ethyl-2-(Diacetylmethylthio)-5-methyl-3H-4-oxo-thieno[2,3-
d]pyrimidine-6-carboxy-late (5b)
Compound 5b was obtained by reaction of 3a and 3-chloropentane-
2,4-dione (1.34 g, 0.012 moles). The compound was recrystallized from
dioxane to produce 5b as colorless crystals; IR spectrum (KBr) cm−1
:
3444 (broad NH and OH), 1717 (CO) and 1663 (CO); 1H-NMR (DMSO-
d6) δ ppm: 1.30 (t, 3H, CH3), 2.35 (s, 6H, 2CH3), 2.80 (s, 3H, CH3), 4.30
(q, 2H, CH2), 4.75 (s, 1H, CH) and 8.00 (br s, 1H, NH, D2O exchange-
able); MS (m/z): 368 (M+) 100%.
General Method for Preparation 5c,d
To a warmed ethanolic potassium hydroxide solution [prepared by dis-
solving potassium hydroxide (0.56 g, 0.01 mole) in ethanol (50 ml)] was

2078
H. A. R. Hussein
added compound 3b (2.42 g, 0.01 mole), heated for 30 min; the mixture
was allowed to cool to room temperature, and the proper halo compound
(0.013 mole) was added. The mixture was heated under reflux for 5 h,
then cooled and poured into water. The solid product was filtered-off
and recrystallized from the appropriate solvent to produce 5c,d.
5-Methyl-2-methylthio-3H-4-oxo-thieno[2,3-d]pyrimidine-6-
Carboxylic acid (5c)
Compound 5c was obtained by reaction of 3b and methyl iodide (1.72
g, 0.013 mole). The compound was recrystallized from dioxane to pro-
duce 5c as colorless crystals; IR spectrum (KBr) cm−1: 3448 (NH); 1717
1
(CO) and 1654 (CO); H-NMR (DMSO-d6) δ ppm: 2.80 (s, 3H, CH3),
3.65 (s, 3H,CH3), and 12.90 (s, 1H, OH, D2O exchangeable); MS (m/z):
209.0 (M+-SMe) 100%.
2-(Diacetylmethylthio)-5-methyl-3H-4-oxo-thieno[2,3-
d]pyrimidine—6-carboxylic acid (5d)
Compound 5d was obtained by reaction of 3b and 3-chloropentane-
2,4-dione (1.34 g, 0.012 moles). The compound was recrystallized from
dioxane to produce 5d as colorless crystals; IR spectrum (KBr) cm−1
:
3355 (broad NH and OH), 1704 (CO) and 1655 (CO); 1H-NMR (DMSO-
d6) δ ppm: 2.35 (s, 6H, 2CH3), 2.75 (s, 3H, CH3), 4.35 (s, 1H, CH), 7.45
(s, 1H, NH, D2O exchangeable) and 13.00 (br s, 1H, OH, D2O exchange-
able); MS (m/z): 340 (M+) 58%, 322 (M+-18)100%.
Ethyl-3-Ethyl-2-methylthio-5-methyl-4-oxo-thieno[2,3-
d]pyrimidine-6-carboxylate (6)
To a warmed ethanolic potassium hydroxide solution (prepared by
dissolving (0.56 g, 0.01 mole) in 50 ml ethanol) was added compound 5c
(2.56 g, 0.01 mole). Heating was continued for 30 min and the mixture
was allowed to cool and the proper ethyl iodide (1.86g, 0.012 mole) was
added. The mixture was heated under reflux for 4 h, and then cooled at
room temperature, poured into cold water. The solid so-precipitate was
filtered-off, washed with water, and recrystallized from the appropriate
solvent to give 6 as colorless crystals; IR spectrum (KBr) cm−1: 1715
1
(CO) and 1672 (CO); H-NMR (CDCl3) δ ppm: 1.35 (m, 6H, 2CH3),
2.60 (s, 3H, CH3), 2.90 (s, 3H, CH3), 4.15 (q, 2H, CH2), 4.35 (q, 2H,
CH2), MS (m/z ): 312 (M+) 100%.
General Procedure for Preparation of 7a,b
A solution of compound 5b or 5d (0.01 mole) in (10 ml) acetic anhydride
and (20 ml) of pyridine was heated under reflux for 5 h. The reaction

Azolothienopyrimidines and Thienothiazolopyrimidines
2079
mixture was cooled, the deposited precipitate was filtered-off and re-
crystallized from dioxane to give 7a,b as yellow crystals.
Ethyl-2-Acetyl-3,6-dimethyl-5-oxo-thiazolo[3,2-a]thieno[2,3-
d]pyrimidin-7-carboxyl-ate (7a)
Compound 7a was obtained by heating of 5b (3. 68 g, 0.01 mole) with
(10 ml) acetic anhydride and (20 ml) of pyridine; IR spectrum (KBr)
1
cm−1: 1740 (CO), 1694 (CO) and 1668 (CO); H-NMR (DMSO-d6)
δ
ppm: 1.30 (t, 3H, CH3), 2.65 (s, 3H, CH3), 2.75 (s, 3H, CH3), 3.10 (s, 3H,
CH3), 4.30 (q, 2H, CH2); MS (m/z): 350 (M+) 100%.
2-Acetyl-3,6-dimethyl-5-oxo-thiazolo[3,2-a]-thieno[2,3-
d]pyrimidin-7-carboxylic acid (7b)
Compound 7b was obtained by heating of 5d (3.40 g, 0.01 mole) with
(10 ml) acetic anhydride and (20 ml) of pyridine; IR spectrum (KBr)
cm−1: 3446(OH), 1716 (CO), 1683 (CO) and 1663 (CO); 1H-NMR (DMSO-
d6) δ ppm: 2.60 (s, 3H, CH3), 2.85 (s, 3H, CH3) 3.15 (s, 3H, CH3) and
12.95(1H, OH, D2O exchangeable); MS (m/z): 322(M+) 100%.
General Procedure for Preparation of 8a,b
A mixture of 5a or 5c (0.01 mole) and hydrazine hydrate (99–100%)
(7 ml, 0.03 mole) in dioxane and ethanol was heated under reflux for
5 h. The reaction mixture was cooled and filtered-off and recrystallized
from proper solvent to produce 8a,b as colorless crystals
Ethyl-2-Hydrazino-5-methyl-3H-4-oxo-thieno[2,3-
d]pyrimidine-6-carboxylate (8a)
Compound 8a was obtained by reaction of 5a (2.84 g, 0.01 mole) and
hydrazine hydrate. The product recrystallized from dioxane; IR spec-
trum (KBr) cm−1: 3341; 3178 [(NH2), (NH)]; 1707 (CO) and 1667 (CO);
1H-NMR (DMSO-d6) δ ppm: 1.35 (t, 3H, CH3), 2.80 (s, 3H, CH3), 4.40
(q, 2H, CH2), 4.60 (br, 2H, NH2, D2O exchangeable), and 8.20 (br s, 1H,
NH, D2O exchangeable); MS (m/z): 268 (M+) 100%.
2-Hydrazino-5-methyl-3H-4-oxo-thieno[2,3-d]pyrimidine-6-
Carboxylic Acid (8b)
Compound 8b was obtained by reaction of 5c (2.56 g, 0.01 mole)
and hydrazine hydrate. The product recrystallized from dimethylfor-
mamide; IR spectrum (KBr) cm−1: 3270; 3177 [(NH2), (NH)]; 1690 (CO)
and 1660 (CO); 1H-NMR (DMSO-d6) δ ppm: 2.75 (s, 3H, CH3), 5.00 (br,
2H, NH2, D2O exchangeable), 8.20 (br s, 1H, NH, D2O exchange-able),

2080
H. A. R. Hussein
and 12.90 (s, 1H, OH, D2O exchangeable); MS (m/z): 240(M+) 43%; 196
(M+-COOH)100%.
General Procedure for Preparation of 9a,b
A mixture of 7b (2.40 g, 0.01 mole) and aliphatic acid was heated under
reflux for 6 h. The reaction mixture was allowed to cool to room tem-
perature and poured into water. The solid product so precipitated was
filtered off and recrystallized from dioxane to produce 9a,b as colorless
crystals.
6-Methyl-1H-5-oxo-thieno[2,3-d][1,2,4]triazolo[4,3-
a]pyrimidin-7-Carboxylic Acid (9a)
Compound 9a was obtained by heating compound 7b and formic acid
(30 ml) with a catalytic amount of concentrated hydrochloric acid; IR
spectrum (KBr) cm−1: 3430(OH), 3138 (NH), 1686 (OH) and 1654 (CO);
1H-NMR (DMSO-d6) δ ppm: 2.45 (s, 3H, CH3), 6.75 (s, 1H, CH), 9.10
(s, 1H, NH, D2O exchangeable), and 11.90 (1H, OH, D2O exchangeable);
MS (m/z): 250(M+) 100%.
3,6-Dimethyl-1H-5-oxo-thieno[2,3-d][1,2,4]triazolo[4,3-
a]pyrimidin-7-Carboxylic acid (9b)
Compound 9b was obtained by heating compound 7b and glacial
acetic acid (30 ml), IR spectrum (KBr) cm−1: 3420(OH), 3115 (NH),
1
1681 (CO) and 1651 (CO), H-NMR (DMSO-d6) δ ppm: 1.90 (s, 3H,
CH3), 2.75 (s, 3H, CH3), 9.95 (s, 1H, NH, D2O exchangeable), and 11.55
(1H, OH, D2O exchangeable); MS (m/z): 264(M+) 100%.
General procedure for preparation of 10a–c
A mixture of compound 7b (2.40 g, 0.01 mole) and the appropriate β-
diketone (0.01 mole) was heated under reflux in absolute ethanol (30 ml)
for 5 h. The reaction mixture was allowed to cool to room temperature.
The precipitate solid was collected by filtration, dried and recrystallized
from dioxane to produce 10a–c.
2(3,5-Dimethyl-pyrazol-1-yl)-5-methyl-3H-4-oxo-thieno[2,3-
d]pyrimidin-6-Carboxy-lic Acid (10a)
Compound 10a was obtained by heating compound 7b and pentane-
2,4-dione (1.00 g, 0.01 mole). The product was recrystallized from
dioxane to produce 10a as pale yellow crystals; IR spectrum (KBr)
cm−1: 3435(OH), 3130 (NH), 1688 (CO) and 1655 (CO); 1H-NMR

Azolothienopyrimidines and Thienothiazolopyrimidines
2081
(DMSO-d6) δ ppm: 2.25 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.80 (s, 3H,
CH3), 6.30 (s, 1H, CH), 6.65 (s, 1H, NH, D2O exchangeable), and 11.90
(brs, 1H, OH, D2O exchangeable); MS (m/z): 304 (M+) 100%.
2(3,5-Dimethyl-4-chloropyrazol-1-yl)-5-methyl-3H-4-oxo-
thieno[2,3-d]pyrimidin-6-carboxylic Acid (10b)
Compound 10b was obtained by heating compound 7b and 3-
chloropentane-2,4-dione (1.34 g, 0.01 mole). The product was recrys-
tallized from dioxane to produce 10b as orange crystals; IR spectrum
(KBr) cm−1: 3440(OH), 3120 (NH), 1683 (CO) and 1655 (CO); 1H-NMR
(DMSO-d6) δ ppm:, 2.35 (s, 3H, CH3), 2.55 (s, 3H, CH3), 2.85 (s, 3H,
CH3), 10.20 (s, 1H, NH, D2O exchangeable)and 11.45 (brs, 1H, OH, D2O
exchangeable); MS (m/z): 340, 342[M+, (84%, 39.%)].
2(3-Trifluoro,5-methyl-pyrazol-1-yl)-5-methyl-3H-4-oxo-
thieno[2,3-d]pyrimidin-6-carboxylic Acid (10c)
Compound 10c was obtained by heating compound 7b and 1,1,1-
trifluoro-2,4-pentandione (1.54 g, 0.01 mole). The precipitated solid was
collected by filtration, dried and recrystallized from dioxane to produce
10c, as pale yellow crystals,; IR spectrum (KBr) cm−1: IR spectrum
(KBr) cm−1: 3445(OH), 3130 (NH), 1689 (CO) and 1658 (CO); 1H-NMR
(DMSO-d6) δ ppm: 2.30 (s, 3H, CH3), 2.85 (s, 3H, CH3), 6.70 (s, 1H,
CH), 9.15 (s, 1H, NH, D2O exchangeable)and 14.00 (brs, 1H, OH, D2O
exchangeable); MS (m/z): 360 [M+, (84%, 39.%)].
General Procedure for Preparation of 11a,b
A mixture of compound 7b (2.40 g, 0.01 mole), and the appropriate
aromatic aldehyde (0.01 mole), dioxane (30 ml), and a catalytic amount
of piperidine was heated under reflux for 6 h. The reaction mixture was
allowed to cool to room temperature, and then it was poured into water.
The formed precipitate was filtered-off, washed with water, dried and
recrystallized from dimethylformamide to produce 11a,b.
2-(4-Chlorophenylmethylenehydrazone)-5-methyl-3H-4-oxo-
thieno[2,3-d]pyrimidin-6-carboxylic acid (11a)
Compound 11a was obtained by heating compound 7b and 4-
chlorobenzaldehyde (1.40 g, 0.01 mole). The product was recrystallized
from dimethylformamide to produce 11a as yellow crystals; IR spec-
trum (KBr) cm−1: 3475 (OH), 3180 (NH), 3135 (NH) 1685 (CO) and
1665 (CO); 1H-NMR (DMSO-d6) δ ppm: 2.85 (s, 3H, CH3), 7.50 (d, 2H,
aromatic protons), 8.00 (t, 3H, aromatic protons + CH), 11.25 (br s, 1H,
NH, D2O exchangeable), 12.00 (br s, 1H, NH, D2O exchangeable), and

2082
H. A. R. Hussein
12.90 (brs, 1H, OH, D2O exchangeable); MS (m/z): 362, 264 [M+, (100%,
24.%)].
2-(4-Methoxyphenylmethylenehydrazone)–5-methyl-3H-4-
oxo-thieno[2,3-d]pyrami-din-6-carboxylic Acid (11b)
Compound 11b was obtained by heating compound 7b and 4-
methoxybenzaldehyde (1.36 g, 0.01 moles). The product was recrystal-
lized from dimethylformamide to produce 11b as yellow crystals; IR
spectrum (KBr) cm−1: 3440 (OH), 3135 (NH), 3125 (NH) 1690 (CO) and
1675 (CO); 1H-NMR (DMSO-d6) δ ppm: 2.80 (s, 3H, CH3), 3.75 (s, 3H,
CH3), 6.95 (d, 2H, aromatic protons), 7.95 (d, 2H, aromatic protons),
8.05 (s, 1H, CH), 8.80 (br s, 1H, NH, D2O exchangeable), and 11.85
(brs, 1H, OH, D2O exchangeable); MS (m/z): 358 (M+) 100%.
2-Ethylacetoacetatehydrazon-3H-4-oxo-
thieno[2,3-d]pyrimidin-6-carboxylic Acid (12)
A mixture of compound 7b (2.40 g, 0.01 mole) and ethyl acetoacetate
(1.30 g, 0.01 mole) was heated under reflux in absolute ethanol for 5 h.
The reaction mixture was allowed to cool to room temperature. The pre-
cipitate so-formed was collected by filtration, dried, and recrystallized
from ethanol to produce 12 as colorless crystals; IR spectrum (KBr)
cm−1: 3421 (broad OH and NH), 1716 (CO), 1676 (CO) and 1652 (CO);
1H-NMR (CDCl3) δ ppm: 1.25 (m, 3H, CH3), 2.00 (s, 3H, CH3), 2.75 (s,
3H, CH3), 3.40 (s, 2H, CH2), 4.10 (q, 3H, CH2+ NH, D2O exchangeable),
10.75 (brs, 1H, NH, D2O exchangeable), and 10.80 (brs, 1H, OH, D2O
exchangeable); MS (m/z): 352(M+) 100%.
5-Methyl-2-(3-methyl-5-oxo-4H-pyrazol-1-yl)-3H-4-oxo-
thieno[2,3-d]pyrimidin-6-Carboxylic Acid (13)
Method A. A solution of compound 7b (2.40 g, 0.01 mole) and ethyl
acetoacetate (1.30 g, 0.01 mole) in sodium ethoxide solution (prepared
by dissolving sodium metal (0.23 g, 0.01 mole) in absolute ethanol
(30 ml)) was heated under reflux for 5 h. The reaction mixture was al-
lowed to cool to room temperature, poured into water, and neutralized
by dilute acetic acid solution. The solid product so precipitated was fil-
tered off, dried and recrystallized from dimethylformamide to produce
13 as colorless crystals.
Method B. A solution of compound 12 (3.52 g, 0.01 mole) was heated
under reflux with sodium ethoxide solution (prepared by dissolving
sodium metal (0.23 g, 0.01 mole) in absolute ethanol (30 ml)) for 5
h. The reaction mixture was allowed to cool to room temperature
then poured into water and neutralized by dilute acetic acid solution.

Azolothienopyrimidines and Thienothiazolopyrimidines
2083
TABLE II Physical Data for the Products 1–13
Elemental analyses
(calcd./ found )
Comp. no.
m.p.◦C
Yield %
80
M.F. (M.wt.)
%C
%H
%N
1
103–105
C11H15NO4S
257.31
51.35
51.80
45.55
45.40
44.43
44.40
39.66
39.50
57.27
57.20
56.06
56.00
52.71
52.71
55.12
55.10
53.99
53.90
50.43
50.43
49.31
49.25
46.46
46.40
48.90
48.85
42.17
42.10
45.87
45.86
49.98
49.96
44.76
44.74
39.99
39.95
51.41
51.41
48.43
48.40
43.19
43.15
45.45
45.40
5.83 5.44
5.50 5.40
5.09 8.85
5.00 8.75
3.72 10.36
3.70 10.30
2.49 11.56
2.45 11.55
3.54 7.03
3.50 7.03
3.76 14.96
3.75 14.85
3.02 6.47
3.02 6.47
2.72 7.56
2.72 7.55
3.02 6.99
3.00 6.95
2.24 6.91
2.20 6.88
2.06 6.39
2.06 6.35
4.25 9.85
4.25 9.83
4.37 7.60
4.37 7.55
3.14 10.93
3.14 10.90
3.55 8.23
3.54 8.20
5.16 8.96
5.10 8.94
4.50 20.88
4.47 20.85
3.35 23.32
3.34 23.30
4.02 7.99
4.00 7.96
3.13 8.70
3.10 8.65
2.42 22.39
2.42 22.39
3.05 21.20
3.00 21.20
2
200–202
240–242
288–290
260–262
275–277
265–267
312–314
319–321
325–327
354–356
275–277
255–257
300–302
285–287
268–270
278–280
290–292
219–221
330–332
263–265
300–302
75
80
75
73
70
75
65
60
65
65
85
80
80
75
80
75
70
80
70
85
80
C
12H16N2O4S2
316.40
10H10N2O3S2
270.34
3a
3b
4a
4b
4c
4d
4e
4f
C
C8H6N2O3S2
242.28
C19H14N2O4S2
398.46
C20H16N2O5S2
428.49
C
19H13ClN2O4S2
432.91
C
17H10N2O4S2
370.41
18H12N2O5S2
400.43
C
C17H9ClN2O4S2
404.85
C18H9FN2O4S2
438.41
C11H12N2O3S2
284.36
C
4g
5a
5b
5c
5d
6
15H16N2O5S2
368.43
C9H8N2O3S2
256.31
C13H12N2O5S2
340.38
C13H16N2O3S2
312.42
C
7a
7b
8a
8b
9a
9b
10H12N4O3S
268.30
C8H8N4O3S
240.24
C15H14N2O4S2
350.42
C13H10N2O4S2
322.37
C9H6N4O3S
250.24
C
10H8N4O3S
264.27
(Continued on next page)

2084
H. A. R. Hussein
TABLE II Physical Data for the Products 1–13 (Continued)
Elemental analyses
(calcd./ found )
Comp. no.
m.p.◦C
Yield %
75
M.F. (M.wt.)
%C
%H
%N
10a
340–342
C13H14N4O3S
306.34
13H13ClN4O3S
340.79
13H11F3N4O3S
360.31
C15H11ClN4O3S
362.79
51.00
51.00
45.81
45.80
43.33
43.33
49.66
49.62
53.62
53.60
47.72
47.70
47.06
47.00
4.60
4.55
3.84
3.84
3.07
3.05
3.05
3.05
3.93
3.90
4.57
4.50
3.29
3.25
18.28
18.25
16.44
16.40
15.55
15.50
15.44
15.42
15.63
15.60
15.90
15.90
18.30
18.30
10b
10c
11a
11b
12
300–302
310–312
305–307
315–317
230–232
302–304
75
70
75
80
85
60
C
C
C
C
C
16H14N4O4S
358.38
14H16N4O5S
352.37
12H10N4O4S
306.30
13
The precipitate so-formed was collected by filtration, dried and recrys-
tallized from dimethylformamide to produce 13 as colorless crystals.
IR spectrum (KBr) cm−1: 3446 (OH) 1685 (CO), 1665 (CO) and 1654
(CO). .1H-NMR (DMSO-d6) δ ppm: 2.65 (s, 3H, CH3), 2.75 (s, 3H, CH3),
4.00 (s, 2H, CH2), and 12.50 (brs, 1H, OH, D2O exchangeable); MS (m/z):
306(M+) 100%.
CONCLUSIONS
This work is concerned with the synthesis and reactions of thieno[2,3-
d]pyrimidone with functional and bifunctional groups to give pyra-
zolothieno, thiazolothieno, and triazolo thieno[2,3-d]pyrimidine deriva-
tives. Those reactions carrying out transformation, which in one or two
steps added a new heterocyclic ring to the molecules
REFERENCES
[1] C. J. Shishoo and K. S. Jain, J. Heterocyclic Chem., 29, 883 (1992).
[2] J. Clark, M. S. Shahhet, D. Kovakas, and G. Varvounis, J. Heterocyclic Chem., 30,
1065 (1993).
[3] F. Sauter,W. Deinhammer, and P. Stanetty, Manatsh. Chem., 105(6), 1258–1265
(1974).
[4] U. S. Pathak, S. Singh, and J. Padh, Indian J. Chem., Section B, 30, 618 (1992).

Azolothienopyrimidines and Thienothiazolopyrimidines
2085
[5] C. J. Shishoo, M. B. Devani, V. S. Bhadti, K. S. Jain, I. S. Rathod, R. K. Goyal, T. P.
Gandhi, R. B. Patel, and S. R. Naik, Arzneim-Forsch, 40, 567 (1990).
[6] K. Gewald, E. Schinke, and H. Bottcher, Ber.,99, 94 (1966).
[7] M. B. Devani, C. J. Shishoo, U. S. Pathak, S. H. Parikh, G. F. Shah, and A. C. Padhya,
J. Pharmaceutical Science., 65, 660 (1976).
[8] D. N. Muanza, B. W. Klm, K.L. Euler, and L. J. Williams, Pharmacog, 32, 337, (1994).
[9] O. N. Irob, M. Moo-Young, and W. A. Anderson, J. Pharmacog., 34, 87, (1996).