Synthesis, reactions, and antimicrobial evaluation of some polycondensed thienopyrimidine derivatives

Article abstract of DOI:10.1080/00397910903050954

Some novel indeno[2,1-b]thiophenes, indeno[1',2':4,5]thieno[2,3-d][1,2,3] triazines, indeno[1',2':4,5]thieno[2,3-d]pyrimidines, indeno[1',2':4,5]thieno[2, 3-d][1,3]thiazolo[3,2-a]pyrimidines, and indeno[1',2':4,5]thieno[2,3-d][1,2,4] triazolo[4,3-a]pyrimidines 2-16 were prepared starting with 2-aminoindeno[2,1-b] thiophene-3-carboxylic acid amide (1). Furthermore, the antimicrobial evaluation of the prepared products showed that many of them revealed promising antimicrobial activity.

Full text of DOI:10.1080/00397910903050954

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Synthesis, Reactions, and Antimicrobial
Evaluation of Some Polycondensed
Thienopyrimidine Derivatives
Aymn E. Rashad a , Ahmed H. Shamroukh a , Randa E. Abdel-Megeid a
& Wael A. El-Sayed a
a Photochemistry Department, National Research Centre, Dokki,
Cairo, Egypt
Version of record first published: 12 Mar 2010.
To cite this article: Aymn E. Rashad , Ahmed H. Shamroukh , Randa E. Abdel-Megeid & Wael
A. El-Sayed (2010): Synthesis, Reactions, and Antimicrobial Evaluation of Some Polycondensed
Thienopyrimidine Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:8, 1149-1160
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Synthetic Communications1, 40: 1149–1160, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903050954
SYNTHESIS, REACTIONS, AND ANTIMICROBIAL
EVALUATION OF SOME POLYCONDENSED
THIENOPYRIMIDINE DERIVATIVES
Aymn E. Rashad, Ahmed H. Shamroukh,
Randa E. Abdel-Megeid, and Wael A. El-Sayed
Photochemistry Department, National Research Centre, Dokki, Cairo, Egypt
Some novel indeno[2,1-b]thiophenes, indeno[10,20:4,5]thieno[2,3-d][1,2,3]triazines, indeno
[10,20:4,5]thieno[2,3-d]pyrimidines, indeno[10,20:4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyri-
midines, and indeno[10,20:4,5]thieno[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines 2–16 were
prepared starting with 2-aminoindeno[2,1-b]thiophene-3-carboxylic acid amide (1). Further-
more, the antimicrobial evaluation of the prepared products showed that many of them revealed
promising antimicrobial activity.
Keywords: Antimicrobial evaluation; indeno[2,1-b]thiophenes; indenothienopyrimidines; thiazolothieno-
pyrimidines; thienotriazolopyrimidines
INTRODUCTION
Fused thieno[2,3-d]pyrimidine derivatives are one of the most active classes of
compounds because of their synthetic and effective biological importance.[1–3] They
bear structural analogy and isoelectronic relation to purine and several substituted
thieno[2,3-d]pyrimidine derivatives shown to exhibit prominent and versatile bio-
logical activities.[4,5] Recently, many of their derivatives have been synthesized as
potential anticancer,[6] analgesic,[7] antimicrobial,[8] and antiviral agents.[9] Besides,
prominent biological activities have been reported for [1,4]thiazolo[4,3-a]pyrimidine
and [1,2,4]triazolopyrimidine derivivatives, such as antimicrobial,[10,11] analgesic,[12]
and anti-inflammatory[13] activities. This work aimed to synthesize new compounds
related to indeno[10,20:4,5]thieno[2,3-d]pyrimidine derivatives and their fused
[1,3]thiazolo[3,2-a]pyrimidine and [1,2,4]triazolo[4,3-a]pyrimidine derivatives, and
to evaluate their antimicrobial activity.
RESULTS AND DISCUSSION
The starting material 2-aminoindeno[2,1-b]thiophene-3-carboxylic acid amide
(1) was prepared[14] and then underwent cyclization with butyraldehyde or benzoyl
chloride to afford thieno[2,3-d]pyrimidinone derivatives 2 and 3, respectively.
Received March 25, 2009.
Address correspondence to Aymn E. Rashad, Photochemistry Department, National Research
Centre, Dokki, Cairo, Egypt. E-mail: aymnelzeny@yahoo.com
1149

1150
A. E. RASHAD ET AL.
Analytical and spectral data of the aforementioned compounds are in agreement
with the proposed structures (Experimental). In particular, the presence of propyl
signals and phenyl signals in the 1H NMR spectra of compounds 2 and 3 confirmed
their structures.
Some reports[15,16] stated that the reaction of compounds analogous to com-
pound 1 with nitrous acid gave the diazonium chloride derivative, which on boiling
in alcohols gave unexpected carboxylic acid alkyl esters. Meanwhile, our attempts
to cyclize compound 1 by stirring with nitrous acid gave the corresponding triazinone
derivative 4 (Scheme 1). The structure of compound 4 was confirmed with spectral
data, where its infrared (IR) spectrum showed bands at (n, cmꢀ1): 3201 (NH)
1
=
and 1678 (C O) and its H NMR spectrum showed a signal at d 8.14 ppm for NH.
Also, mass spectrometry (MS) gave the molecular ion peak at m=z 241 (Mþ, 74%)
(Experimental). Moreover, treatment of compound 1 with ethyl chloroformate in
dry dioxane under reflux afforded not only the cyclized thieno[2,3-d]pyrimidindione
derivative 5 but also a product assigned to the structure of compound 6. Refluxing
compound 6 in dry pyridine or compound 1 with ethyl chloroformate in dry pyridine
gave in both cases the same product, which was assigned to the structure of com-
pound 5 (Scheme 1, Experimental). The pyrimidindione derivative 5 could be formed
Scheme 1. Synthesis route of compounds 2–9.

POLYCONDENSED THIENOPYRIMIDINE DERIVATIVES
1151
via the formation of derivative 6, which was isolated and suffered cyclization to
thieno[2,3-d]pyrimidindione derivative 5 under the conditions of the reaction
(Scheme 1). Inspection of the IR spectrum of product 5 revealed the presence ofþ2
=
NH and 2 C O signals, and MS gave the molecular ion peak at m=z 256 (M ,
1
100%). Moreover, the H NMR spectrum of product 6 showed signals at d 1.05
and 4.05 ppm for CH3 and CH2, respectively (Experimental).
However, heating of compound 1 with phenyl isothiocyanate in dry pyridine
gave a mixture of the thiourea derivative 8 in addition to the corresponding thioxo
derivative 7. Analytical and spectral data of the aforementioned compounds are in
agreement with the proposed structures (see Experimental). Alkaline treatment of
compound 8 with potassium hydroxide did not afford a product assigned to the
structure of compound 7 but instead afforded the cyclized 3-phenyl thieno[2,3-d]pyr-
imidindione derivative 9. Inspection of the IR spectrum of product 9 revealed the
=
presence of NH and 2 C O signals, and MS gave the molecular ion peak at m=z
1
332 (Mþ, 100%). Moreover, the H NMR spectrum of product 9 showed signals
of NH and phenyl groups at d 8.36 and 6.80–7.32 ppm, respectively (Experimental).
The formation of the unexpected 3-phenyl thieno[2,3-d]pyrimidindione derivative 9
was obtained via formation of the thioxo derivative 7 at first, which on further boil-
ing gave the corresponding pyrimidindione derivative 9.[17]
When compound 1 was heated under reflux temperature with carbon disul-
phide, it gave the corresponding 2-thioxo derivative 10. Its IR spectrum revealed
the presence of NH and C O signals, and 1H NMR spectrum gave signals at
=
3.20–3.40 and 12.52 ppm that were exchangeable with D2O for SH and NH, respect-
ively. Meanwhile, when compound 10 was refluxed with chloroacetic acid in a
mixture of acetic acid–acetic anhydride (3:1), it afforded the corresponding thiazo-
lothienopyrimidine derivative 11 (Scheme 2). The IR spectrum of compound 11
=
revealed the absence of the NH, as well as the presence of 2 C O signals (Experi-
mental). Also, 13C NMR spectrum showed the presence of the methylene group in
=
addition to the 2 C O groups.
Methylation of compound 10 with methyl iodide in alcoholic potassium
1
hydroxide solution afforded the corresponding 2-methylthio derivative 12. The H
NMR spectrum of compound 12 showed the presence of methyl group at d
2.40 ppm in addition to the peak corresponding to the NH group at d 7.51 ppm.
Its 13C NMR spectrum showed the presence of the methyl group in addition to
=
the absence of the peak corresponding to C S.
Hydrazinolysis of compound 12, in ethanol, gave 2-hydrazino-3,9-dihydro-
1
indeno[10,20:4,5]thieno[2,3-d]pyrimidin-4-one (13) (Scheme 2). The H NMR spec-
trum of compound 13 gave signals for NH, NH2, exchangeable with D2O, and its
MS gave the molecular ion peak at m=z ¼ 270 (Mþ, 84%).
Furthermore, the structure of compound 13 was confirmed chemically by treat-
ment with formic acid to afford the corresponding thieno[3,2-d][1,2,4]triazolo[4,3-a]-
pyrimidine 14. The IR and 1H NMR spectra of compound 14 showed signals for NH,
and its MS gave the molecular ion peak as a base peak at m=z¼ 280 (Experimental).
However, heating of compound 10 with ethyl chloroacetate in alcoholic potass-
ium hydroxide solution gave a product assigned to the structure of compound 15.
The 1H NMR and13C NMR spectra of the latter compound revealed two methylene
signals in addition to methyl signals (Experimental).

1152
A. E. RASHAD ET AL.
Scheme 2. Synthesis route of compounds 10–16.
Moreover, hydrazinolysis of compound 15, in ethanol, gave the acid hydrazide
16 (Scheme 2). Inspection of the IR and 1H NMR spectra of product 16 revealed the
presence of NH and NH2 signals, and its MS gave the molecular ion peak at m=z 344
(Mþ, 65%) (Experimental).
Antimicrobial Activity
The in vitro antimicrobial activity of the synthesized compounds was investi-
gated against several pathogenic Gram-positive bacteria (Bacillus subtilis),
Gram-negative bacteria (Escherichia coli), fungi (Aspergillus niger), and yeast
(Candida albicans). All microorganisms were obtained from the culture collection
of the Department of Natural and Microbial Products, National Research Centre,
Dokki, Cairo, Egypt.
Method[18]
The cap-assay procedure using (g=L) peptone (6), yeast extract (3), meat
extract (1.5), glucose (1), and agar (20) was used. The medium was sterilized and div-
ided while hot (50–60 ꢁC) in 15-mL portions among sterile Petri dishes 9 cm in diam-
eter. One mL of the spore suspension of each microorganism was spread all over the
surface of the cold solid medium placed in the Petri dish. Each of the tested com-
pounds (0.5 g) was dissolved in 5 mL of dimethylformamide. An amount of 0.1 mL
of test solution was placed on Whatman paper discs 9 mm in diameter, and the sol-
vent was left to evaporate. These saturated discs were placed carefully on the surface

POLYCONDENSED THIENOPYRIMIDINE DERIVATIVES
1153
of the inoculated solid medium; each Petri dish contains at least three discs. The Petri
dishes were incubated at 5 ꢁC for 1 h to permit good diffusion, transferred to an incu-
bator at 85 ꢁC overnight, and then examined. The results were recorded by
measuring the inhibition zone diameters. Dimethylsulfoxide (DMSO) as a solvent
showed no inhibition zones. The results were compared to streptomycin and fusidic
acid as reference drugs.
Results
As shown in Table 1, the antimicrobial activity of the tested compounds was
evaluated by measuring the zone diameters, and the results were compared with
those of well-known drugs (standards). In general, the tested compounds showed
promising antimicrobial activity against bacteria more than fungi or yeast. Among
the tested compounds, the substituted thiophene derivatives 1, 6, and 8 had the most
significant antimicrobial activities. However, fusing a pyrimidine ring to the thio-
phene derivatives to form thieno[2,3-d]pyrimidine derivative as in compounds 2, 3,
5, 7, 9, 10, 12, 13, 15, and 16 or a triazine ring to form a thieno[2,3-d][1,2,3]triazine
derivative as in compound 4 decreased the antimicrobial activity. However,
increased antimicrobial activity was achieved by fusing a thiazole or a triazole ring
to thieno[2,3-d]pyrimidine ring system in compounds 11 and 14, respectively.
Table 1. Antimicrobial activity of the prepared compounds
Disc diffusion test (mm)a
Bacteria
Tested compounds and
standards (mg=mL,
lot. no., bioanalyse)
Gram negative
(Escherichia coli) (Bacillus subtillis) (Aspergillus nigrer) (Candida albicans)
Gram positive
Fungi
Yeast
Streptomycin (10,30225)
Fusidic acid (10,30301)
þþþ
—
þþþ
—
þ
þþþ
þ
þþþ
þþþ
þþ
þ
1
2
þþþ
þ
þþþ
þ
þ
3
þ
þ
—
þ
—
4
þþ
þ
þþ
þ
þ
5
—
þþ
—
þ
—
6
þþþ
þ
þþþ
þ
þþ
—
7
8
þþþ
þ
þþþ
—
þþ
—
9
—
—
—
þ
10
11
12
13
14
15
16
þþ
þþþ
þ
þ
þ
þþþ
þ
þ
þ
þ
þ
—
þ
—
þ
þþþ
þ
þþþ
þ
—
—
—
þ
þ
þ
a
þþþ, highly sensitive (21–25 mm); þþ, fairly sensitive (16–20 mm); þ, slightly sensitive (15–10 mm);
—, not sensitive (0–5 mm).

1154
A. E. RASHAD ET AL.
EXPERIMENTAL
All melting points were uncorrected and measured using an Electro-thermal IA
9100 apparatus (Shimadzu, Japan). Microanalytical data were performed on a Vario
El-Mentar apparatus (Shimadzu, Japan), National Research Centre, Cairo, Egypt.
The IR spectra (KBr) were recorded on a Perkin-Elmer 1650 spectrophotometer,
1
National Research Centre, Cairo, Egypt. H NMR and 13C NMR spectra were
determined on a Varian Mercury (300 MHz) spectrometer (Varian, UK), and the
chemical shifts were expressed in parts per million (ppm) relative to tetramethylsilane
(TMS) as internal reference, Faculty of Science, Cairo University, Egypt. Mass spec-
tra were recorded on a 70-eV EI Ms-QP 1000 EX (Shimadzu, Japan), National
Research Centre, Cairo, Egypt.
Compound 1 was prepared according to a reported method.[14]
2-Propyl-3,9-dihydroindeno[10,20:4,5]thieno[2,3-d]pyrimidin-4-one (2)
An equimolar amount of compound 1 (0.23 g, 0.001 mol) and butyraldehyde
(0.002 mol, 0.14 mL) in glacial acetic acid (30 mL) was refluxed for 10 h. The formed
solid was filtered hot, dried, and recrystallized from dimethylformamide to give com-
pound 2 (0.24 g, 85.71%); mp 228–230 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3320 (NH),
1
=
1690 (C O); H NMR spectrum (DMSO-d6, d ppm): 1.20 (t, J ¼ 7 Hz, 3H, CH3),
1.80 (m, 2H, CH2), 2.60 (t, J ¼ 8 Hz, 2H, CH2), 3.80 (s, 2H, CH2), 7.20–7.50 (m,
3H, Ar-H), 8.30 (d, J ¼ 9 Hz, 1H, Ar-H), 12.30 (s, 1H, NH, D2O exchangeable);
13C NMR (DMSO-d6, d ppm): 13.8 (CH3), 14.4 (CH2), 35.30 (C-9), 36.6 (CH2),
þ
=
118.90–164.74 (Ar-C), 168.50 (C O). MS, m=z (%): 282 (M , 100). Anal. calcd.
for C16H14N2OS: C, 68.06; H, 5.00; N, 9.92; S, 11.36. Found: C, 67.98; H, 5.04;
N, 9.96; S, 11.29.
2-Phenyl-3,9-dihydroindeno[10,20:4,5]thieno[2,3-d]pyrimidin-4-one
(3)
Benzoyl chloride (0.002 mol, 0.29 mL) was added to a solution of compound 1
(0.23 g, 0.001 mol) in dry dioxane (50 mL) containing five drops of triethyl amine.
The reaction mixture was heated for 3 h. The excess solvent was removed under
reduced pressure, and the formed solid was recrystallized from dioxane to give com-
pound 3 (0.19 g, 62.08%), mp 150–152 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3421 (NH),
1
=
1699 (C O); H NMR spectrum (DMSO-d6, d ppm): 3.80 (s, 2H, CH2), 7.20–7.80
(m, 9H, Ar-H), 7.90 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6, þd
=
ppm): 35.30 (C-9), 118.90–166.22 (Ar-C), 168.50 (C O). MS, m=z (%): 316 (M ,
100). Anal. calcd. for C19H12N2OS: C, 72.13; H, 3.82; N, 8.85; S, 10.14. Found:
C, 72.02; H, 3.90; N, 8.79; S, 10.21.
3,9-Dihydroindeno[10,20:4,5]thieno[2,3-d][1,2,3]triazin-4-one (4)
To a solution of compound 1 (0.23 g, 0.001 mol) in hydrochloric acid (20 mL) at
0–5 ꢁC, a solution of sodium nitrite (0.10 g) in water (2 mL) was added over 20 min.
Then the reaction mixture was stirred at 20–25 ꢁC for 2 h, cooled, filtered off, dried,
and recrystallized from dioxane to give compound 4 (0.19 g, 79%); mp 155–157 ꢁC.

POLYCONDENSED THIENOPYRIMIDINE DERIVATIVES
1155
IR spectrum (KBr, n, cmꢀ1): 3201 (NH), 1678 (C O); 1H NMR spectrum
(DMSO-d6, d ppm): 4.10 (s, 2H, CH2), 7.18–7.71 (m, 4H, Ar-H), 8.14 (s, 1H, NH,
D2O exchangeable); MS, m=z (%): 241 (Mþ, 74). Anal. calcd. for C12H7N3OS: C,
59.74; H, 2.92; N, 17.42; S, 13.29. Found: C, 59.82; H, 2.88; N, 17.37; S, 13.34.
=
Reaction of Compound 1 with Ethyl Chloroformate
Method A. Ethyl chloroformate (0.002 mol, 0.29 mL) was added to a solution
of compound 1 (0.23 g, 0.001 mol) in dry dioxane (50 mL) containing five drops of
triethyl amine. The reaction mixture was allowed to heat for 5 h, and the excess sol-
vent was removed under reduced pressure. Then the remaining product was purified
on silica gel at 60–80 ꢁC using petroleum ether=ethyl acetate (70 mL=30 mL) to give
compounds 5 (0.11 g, 43.60%) and 6 (0.12 g, 40.40%), respectively.
Method B. Ethyl chloroformate (0.002 mol, 0.29 mL) was added to a solution
of compound 1 (0.23 g, 0.001 mol) in dry pyridine (50 mL). The reaction mixture was
refluxed for 8 h, cooled, poured into water, neutralized with two or three drops of
conc. hydrochloric acid (35%), filtered off, dried, and recrystallized from dioxane
to give compound 5 (0.20 g, 78.12%). Compound 5 obtained from methods A and
B has the same mp, 192–194 ꢁC (mixed mp showed no depression).
Annulation of Compound 6 to 5
Compound 6 (0.10 g, 0.001 mol) was refluxed in 10 mL pyridine for 1 h, cooled,
poured into water, neutralized with two or three drops of conc. hydrochloric acid
(35%), filtered off, dried, and recrystallized from dioxane to give a compound
(0.09 g, 69.23%) identical in all aspects with compound 5 (mp, mixed mp, TLC).
1,3,9-Trihydroindeno[10,20:4,5]thieno[2,3-d]pyrimidine-2,4-dione (5)
Mp 192–194 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3340 (NH), 3333 (NH), 1717
(C O), 1689 (C O); H NMR spectrum (DMSO-d6, d ppm): 4.17 (s, 2H, CH2),
1
=
=
7.16–7.78 (m, 5H, Ar-H þ NH, D2O exchangeable), 10.14 (s, 1H, NH, D2O exchange-
able); 13C NMR (DMSO-d6, d ppm):þ35.30 (C-9), 120.12–156.24 (Ar-C), 164 (C O),
=
=
168.50 (C O). MS, m=z (%): 256 (M , 100). Anal. calcd. for C13H8N2O2S: C, 60.92;
H, 3.15; N, 10.93; S, 12.51. Found: C, 61.01; H, 3.09; N, 11.00; S, 12.45.
(3-Carbamoyl-8H-indeno[2,1-b]thiophen-2-yl)-carbamic Acid Ethyl
Ester (6)
Mp 99–101 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3345, 3200 (NH2), 3193 (NH),
1
=
=
1665 (C O), 1710 (C O); H NMR spectrum (DMSO-d6, d ppm): 1.05 (t, J ¼ 8 Hz,
3H, OCH2CH3), 3.90 (s, 2H, CH2), 4.05 (q, J ¼ 9 Hz, 2H, OCH2CH3), 7.30–7.70
(m, 6H, Ar-H þ NH2, D2O exchangeable), 11.60 (s, 1H, NH, D2O exchangeable);
13C NMR (DMSO-d6, d ppm): 13.80 (CH3), 35.30 (C-8), 56.þ9 (CH2), 118.21–154.14
=
=
(Ar-C), 164.8 (C O), 169.70 (C O). MS, m=z (%): 302 (M , 64). Anal. calcd. for
C15H14N2O3S: C, 59.59; H, 4.67; N, 9.27; S, 10.61. Found: C, 59.66; H, 4.59; N,
9.33; S, 10.54.

1156
A. E. RASHAD ET AL.
Synthesis of Compounds 7 and 8
Compound 1 (0.23 g, 0.001 mol) was added to dry pyridine (50 mL) containing
phenyl isothiocyanate (0.001 mol, 0.26 mL). Then the reaction mixture was refluxed
for 2 h, cooled, poured into water, neutralized with two or three drops of conc.
hydrochloric acid (35%), filtered off, and dried, and the solid product was purified
on silica gel at 60–80 ꢁC using petroleum ether=ethyl acetate (70 mL=30 mL) to give
compounds 7 (0.09 g, 25.86%) and 8 (0.17 g, 46.57%), respectively.
3-Phenyl-2-thioxo-1,9-dihydroindeno[10,20:4,5]thieno[2,3-
d]pyrimidin-4-one (7)
ꢀ1
Mp 150–152 ꢁC. IR spectrum (KBr, n, cm ): 3202 (NH), 1650 (C O), 1340
=
1
=
(C S); H NMR spectrum (DMSO-d6, d ppm): 3.60 (s, 2H, CH2), 7.14–7.49 (m,
9H, Ar-H), 9.82 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6, d ppm):
=
=
35.30 (C-9), 118.90–146.75 (Ar-C), 164 (C O), 170.50 (C S). MS, m=z (%): 348
(Mþ, 100). Anal. calcd. for C19H12N2OS2: C, 65.49; H, 3.47; N, 8.04; S, 18.41.
Found: C, 65.56; H, 3.40; N, 8.11; S, 18.37.
2-(3-Phenyl-thioureido)-8H-indeno[2,1-b]thiophene-3-carboxylic
Acid Amide (8)
Mp 120–122 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3210–3115 (NH2,NH), 1596
1
=
=
(C O), 1327 (C S); H NMR spectrum (DMSO-d6, d ppm): 3.60 (s, 2H, CH2),
4.55 (s, 2H, NH2, D2O exchangeable), 7.20–7.70 (m, 10H, Ar-H þ NH, D2O
exchangeable), 11.03 (s, 1H, NH, D2O exchangeable); MS, m=z (%): 365 (Mþ, 55).
Anal. calcd. for C19H15N3OS2: C, 62.44; H, 4.14; N, 11.50; S, 17.55. Found: C,
62.36; H, 4.20; N, 11.44; S, 17.61.
3-Phenyl-1,9-dihydroindeno[10,20:4,5]thieno[2,3-d]pyrimidin-
2,4-dione (9)
Compound 8 (0.15 g, 0.001 mol) was refluxed in 10 mL ethanol containing 1 N
potassium hydroxide (2 mL) for 1 h, cooled, poured into water, neutralized with two
or three drops of conc. hydrochloric acid (35%), filtered off, dried, and recrystallized
from dioxane to give compound 9 (0.12 g, 36.14%); mp 146–148 ꢁC; IR spectrum (KBr,
1
n, cmꢀ1): 3333 (NH), 1642 (C O), 1586 (C O); H NMR spectrum (DMSO-d6, d
ppm): 3.36 (s, 2H, CH2), 6.80–7.32 (m, 9H, Ar-H), 8.36 (s, 1H, NH, D2O exchange-
able); 13C NMR (DMSO-d6, d ppm): 34.þ62 (C-9), 119.20–156.74 (Ar-C), 164
=
=
=
=
(C O), 170.50 (C O). MS, m=z (%): 332 (M , 100). Anal. calcd. for C19H12N2O2S:
C, 68.66; H, 3.64; N, 8.43; S, 9.65. Found: C, 68.71; H, 3.59; N, 8.50; S, 9.61.
2-Thioxo-1,3,9-trihydroindeno[10,20:4,5]thieno[2,3-d]pyrimidin-4-one
(10)
A solution of compound 1 (0.23 g, 0.001 mol) and potassium hydroxide (0.05 g,
0.001 mol) in ethanol (50 mL) was treated with carbon disulfide (5 mL), and the

POLYCONDENSED THIENOPYRIMIDINE DERIVATIVES
1157
reaction mixture was refluxed for 5 h. After removal of solvent under reduced
pressure, the residual solid was dissolved in water (20 mL) and acidified with hydro-
chloric acid (2 mL, 10%). The separated solid was filtered off, dried, and recrystal-
lized from ethanol to give compound 10 (0.23 g, 86.14%); mp 240–242 ꢁC. IR
1
spectrum (KBr, n, cmꢀ1): 3345 (NH), 3330 (NH), 1665 (C O); H NMR spectrum
=
(DMSO-d6, d ppm): 3.20–3.40 (bs, 1H, SH, D2O exchangeable), 3.90 (s, 2H, CH2),
7.20–7.55 (m, 4H, Ar-H), 12.52 (s, 1H, NH, D2O exchangeable); 13C NMR
=
(DMSO-d6, d ppm): 33.56 (C-9), 119.30–152.16 (Ar-C), 162 (C O). MS, m=z (%):
272 (Mþ, 100). Anal. calcd. for C13H8N2OS2: C, 57.33; H, 2.96; N, 10.29; S,
23.55. Found: C, 57.42; H, 3.00; N, 10.21; S, 23.44.
2,10-Dihydroindeno[10,20:4,5]thieno[2,3-d][1,3]thiazolo[3,2-
a]pyrimidine-3,5-dione (11)
A mixture of compound 10 (0.27 g, 0.001 mol) and chloroacetic acid (0.10 g,
0.001 mol) was refluxed in a mixture of glacial acetic acid=acetic anhydride
(30 mL=10 mL) containing anhydrous sodium acetate (0.25 g, 0.005 mol) for 3 h.
The reaction mixture was cooled and poured into water, and the formed solid was
filtered off, dried, and recrystallized from dimethyl formamide (DMF) to give com-
pound 11 (0.17 g, 55.60%); mp 204–206 ꢁC. IR spectrum (KBr, n, cmꢀ1): 1685
1
=
=
(C O), 1703 (C O); H NMR spectrum (DMSO-d6, d ppm): 3.90 (s, 2H, CH2),
4.20 (s, 2H, CH2), 7.20–7.50 (m, 4H, Ar-H); 13C NMR (DMSO-d6, d ppm): 35.30
=
=
(C-10), 42.12 (C-2), 118.10–146.24 (Ar-C), 168 (C O), 170.50 (C O). MS, m=z
(%): 312 (Mþ, 100). Anal. calcd. for C15H8N2O2S2: C, 57.68; H, 2.58; N, 8.97; S,
20.53. Found: C, 57.74; H, 2.65; N, 8.89; S, 20.44.
2-Methylsulfanyl-3,9-dihydroindeno[10,20:4,5]thieno[2,3-d]pyrimidin-
4-one (12)
A solution of compound 10 (0.27 g, 0.001 mol) and potassium hydroxide (0.05 g,
0.001 mol) in ethanol (50 mL) was treated with methyl iodide (0.001 mol, 0.16 mL),
and the reaction mixture was warmed on a steam bath at 70 ꢁC for 2 h. The formed
precipitate was filtered off, dried, and recrystallized from ethanol to give compound
12 (0.25 g, 88.50%); mp 160–162 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3345 (NH), 1665
1
=
(C O); H NMR spectrum (DMSO-d6, d ppm): 2.40 (s, 3H, SCH3), 3.77 (s, 2H,
CH2), 7.21–7.34 (m, 4H, Ar-H), 7.51 (s, 1H, NH, D2O exchangeable); 13C NMR
(DMSO-d6, d ppm): 12.10 (þCH3), 34.46 (C-9), 118.62–164.12 (Ar-C), 170.50
=
(C O). MS, m=z (%): 286 (M , 92). Anal. calcd. for C14H10N2OS2: C, 58.72; H,
3.52; N, 9.78; S, 22.39. Found: C, 58.79; H, 3.48; N, 9.84; S, 22.42.
2-Hydrazino-3,9-dihydroindeno[10,20:4,5]thieno[2,3-d]pyrimidin-
4-one (13)
A mixture of compound 12 (0.28 g, 0.001 mol) and hydrazine hydrate 99%
(0.004 mol, 1 mL) was refluxed in ethanol (50 mL) for 3 h. The reaction mixture
was evaporated under reduced pressure, and the formed solid was filtered off, dried,
and recrystallized from ethanol to give 13 (0.19 g, 70.40%); mp 180–182 ꢁC. IR
1
spectrum (KBr, n, cmꢀ1): 3250–3110 (NH2,NH), 1696 (C O); H NMR spectrum
=

1158
A. E. RASHAD ET AL.
(CDCl3, d ppm): 3.82 (s, 2H, NH2, D2O exchangeable), 3.94 (s, 2H, CH2), 7.18–7.45
(m, 5H, Ar-H, NH, D2O exchangeable), 9.85 (s, 1H, NH, D2O exchangeable); MS,
m=z (%): 270 (Mþ, 84). Anal. calcd. for C13H10N4OS: C, 57.76; H, 3.73; N, 20.73; S,
11.86. Found: C, 57.82; H, 3.68; N, 20.78; S, 11.79.
1,10-Dihydroindeno[10,20:4,5]thieno[2,3-d][1,2,4]triazolo[4,3-
a]pyrimidin-5-one (14)
Compound 13 (0.27 g, 0.001 mol) was refluxed in formic acid (20 mL) for 15 h,
then the reaction mixture was poured into water, and the formed solid was filtered
off, dried, and recrystallized from ethanol to give 14 (0.16 g, 58.57%), mp
250–252 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3334 (NH), 1643 (CO); 1H NMR spectrum
(CDCl3, d ppm): 3.36 (s, 2H, CH2), 6.90 (s, 1H, C3-H), 7.24–7.54 (m, 4H, Ar-H), 9.85
(s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6, d þppm): 36.58 (C-10),
=
119.45–164.32 (Ar-C), 170.50 (C O). MS, m=z (%): 280 (M , 100). Anal. calcd.
for C14H8N4OS: C, 59.99; H, 2.88; N, 19.99; S, 11.44. Found: C, 60.03; H, 2.95;
N, 19.89; S, 11.38.
(4-Oxo-3,9-dihydroindeno[10,20:4,5]thieno[2,3-d]pyrimidin-
2-ylsulfanyl)-acetic Acid Ethyl Ester (15)
A solution of compound 10 (0.27 g, 0.001 mol) and potassium hydroxide (0.5 g,
0.001 mol) in ethanol (50 mL) was treated with ethyl chloroacetate (0.001 mmol,
0.13 mL), and the reaction mixture was stirred at room temperature for 3 h. The
formed precipitate was filtered off, dried, and recrystallized from ethanol to give
compound 15 (0.35 g, 98.50%), mp 101–103 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3225
1
=
(NH), 1732 (C O). H NMR spectrum (DMSO-d6, d ppm): 1.38 (t, J ¼ 7 Hz, 3H,
OCH2CH3), 3.26 (q, J ¼ 9 Hz, CH2), 3.55 (s, 2H, CH2), 4.23 (s, 2H, CH2),
7.16–7.51 (m, 4H, Ar-H), 7.88 (s, 1H, NH, D2O exchangeable); 13C NMR
(DMSO-d6, d ppm): 13.74 (CH3), 33.95 (CH2S), 35.30 (C-9), 61.12 (CH2O),
þ
=
=
119.90–145.50 (Ar-C), 168.11 (C O), 170.50 (C O). MS, m=z (%): 358 (M , 65).
Anal. calcd. for C17H14N2O3S2: C, 56.96; H, 3.94; N, 7.82; S, 17.89. Found: C,
57.01; H, 4.01; N, 7.75; S, 17.82.
(4-Oxo-3,9-dihydroindeno[10,20:4,5]thieno[2,3-d]pyrimidin-
2-ylsulfanyl)-acetic Acid Hydrazide (16)
Hydrazine hydrate (1 mL, 99%) was added to a solution of compound 15
(0.35 g, 0.001 mol) in ethanol (50 mL), and the reaction mixture was heated on a
water bath for 5 h. After cooling, the precipitated material was filtered off, washed
with water, dried, and recrystallized from dioxane to give compound 16 (0.33 g,
96%), mp 230–232 ꢁC. IR spectrum (KBr, n, cmꢀ1): 3422–3245 (NH2, NH), 1696
1
=
=
(C O), 1634 (C O). H NMR spectrum (DMSO-d6, d ppm): 3.64 (s, 2H, CH2),
4.23 (s, 2H, CH2), 5.47 (bs, 2H, NH2, D2O exchangeable), 7.09–7.55 (m, 5H,
Ar-H, NH, D2O exchangeable), 9.40 (s, 1H, NH, D2O exchangeable); MS, m=z
(%): 344 (Mþ, 65). Anal. calcd. for C15H12N4O2S2: C, 52.31; H, 3.51; N, 16.27; S,
18.62. Found: C, 52.40; H, 3.45; N, 16.30; S, 18.58.

POLYCONDENSED THIENOPYRIMIDINE DERIVATIVES
1159
ACKNOWLEDGMENT
We are grateful to Dr. Hassan M. Awad, Department of Natural and
Microbial Products, National Research Centre, for biological evaluation.
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