Facile syntheses of some thieno[2,3-d] pyrimidine derivatives

Article abstract of DOI:10.1080/10426500802059984

In one-pot synthesis 2-arylidene-5,6,7,8-tetrahydrothiazolo[3,2-a] cyclopenteno-thieno[2,3-d] pyrimidine-3,5-diones (3) were prepared via the reaction of a ternary mixture of 2-thioxo-1,3,4,5,6,7-hexahydr cyclopentinothieno [2,3-d]-4-one (2), chloroacetic acid and a proper aldehyde. Compound 2 reacted with 3-chloropent-2, 4-dione in ethanolic potassium hydroxide yielding the S-acetyl acetone derivative 5f. The latter compound reacted with hydrazine hydrate and phenyl hydrazine yielded the 2-pyrazolthio derivative 10a, b. Compound 5f also underwent cyclization on heating with acetic acid - pyridine solution to give 11. The 2-methylthio derivative 5a, when treated with hydrogen peroxide gave the corresponding oxidized product 9. Copyright Taylor & Francis Group, LLC.

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Facile Syntheses of Some
Thieno[2,3-d] Pyrimidine
Derivatives
A. S. Aly a , Kh. M. Abu-Zied a & Alaa El-Din M.
Gaafar a
a National Research Centre , Dokki, Cairo, Egypt
Published online: 03 Nov 2008.
To cite this article: A. S. Aly , Kh. M. Abu-Zied & Alaa El-Din M. Gaafar (2008)
Facile Syntheses of Some Thieno[2,3-d] Pyrimidine Derivatives, Phosphorus,
Sulfur, and Silicon and the Related Elements, 183:12, 3063-3078, DOI:
10.1080/10426500802059984
To link to this article: http://dx.doi.org/10.1080/10426500802059984
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Phosphorus, Sulfur, and Silicon, 183:3063–3078, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802059984
Facile Syntheses of Some Thieno[2,3-d] Pyrimidine
Derivatives
A. S. Aly, Kh. M. Abu-Zied, and Alaa El-Din M. Gaafar
National Research Centre, Dokki, Cairo, Egypt
In one-pot synthesis 2-arylidene-5,6,7,8-tetrahydrothiazolo[3,2-a] cyclopenteno-
thieno[2,3-d] pyrimidine-3,5-diones (3) were prepared via the reaction of a
ternary mixture of 2-thioxo-1,3,4,5,6,7-hexahydr cyclopentinothieno [2,3-d]-4-one
(2), chloroacetic acid and a proper aldehyde. Compound 2 reacted with 3-
chloropent-2, 4-dione in ethanolic potassium hydroxide yielding the S-acetyl ace-
tone derivative 5f. The latter compound reacted with hydrazine hydrate and phenyl
hydrazine yielded the 2-pyrazolthio derivative 10a, b. Compound 5f also under-
went cyclization on heating with acetic acid—pyridine solution to give 11. The
2-methylthio derivative 5a, when treated with hydrogen peroxide gave the corre-
sponding oxidized product 9.
Keywords 1,3-Diketones; pyrazoleyl; thiazolo; thienopyrimidones
INTRODUCTION
Our interest in thieno [2,3-d] pyrimidine, and their oxo and thioxo
derivatives synthesis, emerges from the numerous reports on their bi-
ological and physiological activities.1–15
We report a facile and convenient route for the synthesis
of polynuclear heterocyclic substituted thienopyrimidone, as thia-
zolothienopyrimidine and pyrazolothienopyrimidine derivatives. Using
1,2,3,5,6,7-hexahydrocyclopentenothieno-[2,3-d]-pyrimi din-4-(4H)one
(2), as starting material.
Thus, heating ethyl 2-amino-4H,5H,6H-cycloheptnothiophene-3-
carboxylate (1), prepared according to Karl Gewald method,16 with
potassium thiocyanate in dry dioxane in presence of concentrated hy-
drochloric acid, followed by cyclization with acetic acid gave compound
2 in good yield.
Received 10 October 2007; accepted 16 March 2008.
Address correspondence to Dr. Khadiga Shaheen, Photochemistry Department, Na-
tional Research Centre, El-Tahrir Street, P.O. Box 12622, Dokki, Cairo, Egypt. E-mail:
khashaheen@hotmail.com
3063

3064
A. S. Aly et al.
The IR spectrum of 2 displayed absorption bands at 3400, 3293 cm−1
(NH), 2904 (CH) and 1670 (CO). Its 1H-NMR spectrum (CDCl3) showed
signals at δ 2.34 (CH2), δ 2.81 (2CH2), δ12.13 (SH) and δ 13.18 (NH).
Furthermore, 13C-NMR spectrum of 2 showed 6 sp2 and 3 sp3 carbon
atoms.
Upon heating under reflux a mixture of 2, chloroacetic acid, and an
aromatic aldehyde in acetic acid and acetic anhydride in the presence
of anhydrous sodium acetate, heterocycles 3a–d were obtained in good
yields (Scheme 1).
SCHEME 1
The structure assignments are based on an independent preparation
of 3a by condensation of 4 with benzaldehyde in acetic acid in presence
of the anhydrous sodium acetate.
Alkylation of compound 2, in ethanolic potassium hydroxide, with
alkyl iodide or chloro-compounds yielded the alkylthio derivatives 5a–f

Facile Syntheses of Some Thieno[2,3-d] Pyrimidine Derivatives
3065
(Scheme 2). Hydrazine hydrate compounds 5a,b gave the 2-hydrazino
derivative 6, which is conclusive for the structure 5a,b.
SCHEME 2
The 2-alkylthio derivatives 5a,b underwent further alkylation on
treatment with alkyl iodide in aqueous ethanolic sodium hydroxide to
give the N-3 alkylated products 7a,b (Scheme 2). Structural assign-
ments of 7 are based on an independent preparation of 7a by methyla-
tion of compound 8 with methyl iodide.17
Oxidation of 5a with hydrogen peroxide in acetic acid yielded struc-
ture 9, rather than its isomeric sulphone derivative 9a. Structure 9
was preferred upon 9a on the basis of 1H-NMR studies. Thus, 1H-NMR
spectra (DMSO-d6) of both 5a and 9 gave the same value for the methyl
group at δ 2.40 ppm, which proves that the oxidation takes place on the
sulfur atom of the thiophene ring only.

3066
A. S. Aly et al.
Compound 5f, reacted as 1,3-diketone with hydrazine hydrate and
phenyl hydrazine, to afford the cyclized products 10a,b respectively
(Scheme 3). The IR spectra of these compounds displayed absorp-
tion bands at 1665 cm−1 (CO). The 1H-NMR spectrum (CF3COOD:
CDCl3/2:1) of 10a, showed signals at δ 2.56 (CH2).
Heating 5f in a mixture of acetic anhydride-pyridine afforded the cy-
clized product 11. The IR spectrum of 11 showed no absorption bands in
1
the NH region. The H-NMR spectrum (CDCl3: DMSO-d6/1:2) showed
signals at δ 2.30 (CH2), δ 2.45 (CH3) δ 2.70 (CH2), and δ 3.00 (CH3). In
the 13C-NMR spectrum, resonances for 9sp2 and 5sp3 hybirdized car-
bon atoms were observed. The mass spectrum showed m/e 304 (100%
SCHEME 3

Facile Syntheses of Some Thieno[2,3-d] Pyrimidine Derivatives
3067
M+) Compound 11 reacted with each of hydroxylamine hydrochloride
and thiosemicarbazide to give derivative 12 and 13 respectively. IR, 1H-
NMR, and mass spectra of 12 gave data, which support the assigned
structures (Experimental section). On the other hand, condensation of
11 with aromatic aldehyde gave 2-cinnamoyl derivatives 14a–c.
The IR spectra of 14b displayed two carbonyl absorption bands at
1700 and 1695 cm−1. The 1H-NMR spectrum (DMSO-d6) of 14b, showed
signals for three methylenic protons at δ 2.40, δ 2.95, δ 3.15 (CH3), and
the AA’BB’ spectrum for aromatic protons at (6.95 and 7.59 (J = 10 Hz).
The vinyl protons appeared at (7.76 and 7.78 (J = 16 Hz) indicating the
trans configuration of the double bond.
EXPERIMENTAL
Solid compounds were recrystallized to constant melting points and
dried in vacuum in drying pistol containing sodium hydroxide. All
melting points are uncorrected and were taken in open capillaries
on a Gallen Kamp Apparatus. Microanalyses were carried out at the
Microanalytical Unite, National Research Centre and Faculty of Sci-
ence, Cairo University. IR spectra were carried out on FT/IR 300 E
1
Jasco using KBr discs. H-NMR spectra were measured in DMSO or
CDCl3, using Joel Ex. 270 NMR spectrometer. Signals were measured
with reference to TMS as an internal standard. The Mass spectra were
recorded on Finigan SSQ 7000 spectrometer. All reactions were followed
up by TLC using CHCl3/MeOH (9:1, v/v) and/or ethyl acetate/Benzene
(7:3) and detected under UV Lamp.
Ethyl-2-amino-4H, 5H, 6H-cyclopentenothiophene-3-
carboxylate (I)
A mixture of cyclopentanone (0.84 g, 0.01 mol), diethylamine (0.73 g,
0.01 mol), ethylcyanoacetate (1.13 g, 0.01 mol), and ethanol (1 mL.) was
stirred at room temperature, then sulfur (0.32 g, 0.01 mol) was added
drop wise, over a period of one h. The reaction mixture was then stirred
at 40◦C for 5 h (the reaction mixture was followed by TLC). The reaction
mixture was left to cool at room temperature overnight to form orange
crystals. The formed crystals were filtered off and recrystallized from
benzene (20 ml) to yield the title product as orange needles (01.61 g,
76%); m.p. 111–112◦C;[C10H13NSO2] (211.3); found C, 56.63%; H,
5.96%; N, 6.63%. requires C, 56.85%; H, 6.20%; N, 6.63%; IR (potas-
sium bromide) cm−1: 3411 (br NH), 2904 (CH) and 1666 (CO); 1H-NMR
(CF3COOD: CDCl3, 1:1) (ppm: 1.30 (t, 3H, CH3), 2.60 (m, 2H, CH2), 2.75

3068
A. S. Aly et al.
(m, 4H, 2CH2), 4.25 (q, 2H, ester CH2), and 5.80 (br s,2H,NH2, D2O ex-
changeable); 13C-NMR (CF3COOD:CDCl3/1:1) (ppm: 14.5 (CH3); 27.3,
28.9, 30.8 and 59.4 (4CH2); 102.8,103.2, 121.4 and, 142.8 (the thiophene
ring carbon atoms) and 166.4 (CO). MS (EI+Q1MS LMR UP LR): 211.0
(M+) 100%.
1, 2, 3, 5, 6, 7-Hexahydrocyclopentenothieno [2,3-d]
pyrimidine-4(4H)-one (2)
Compound 1 (2.11 g, 0.01 mol), potassium thiocyanate (1.94 g, 0.02 mol),
and concentrated hydrochloric acid solution (30 mL) was refluxed in
dioxane (30 mL) for 5 h (the reaction mixture was followed by TLC).
The reaction mixture was cooled and poured into water (100 mL). The
deposited precipitate was filtered off and recrystallized from dioxane
(30 mL). The product was dissolved in 10% sodium hydroxide solution,
and then neutralized with concentrated hydrochloric acid solution to
afford colorless precipitate. The formed precipitate was collected by
filtration, and it was washed with water and recrystallized from diox-
ane (30 ml) to yield the title product as colorless powder (1.64 g, 73%);
mp. 340–42◦C; [C9H8N2S2O] (224.3); found: C, 48.2% 6; H, 3.55%; N,
12.49%. Requires: C, 48.19%; H, 3.59%; N, 12.49%); IR (potassium bro-
mide) cm−1: 3400, 3293 (broad NH), 2904 (CH) and 1670 (CO); 1HNMR
(DMSO-d6) δ ppm: 2.34 (m, 2H, CH2); 2.81 (m, 4H, 2CH2); 12.13 (s, 1H,
SH) and 13.18 (br s, 1H, NH, D2O exchangeable); 13C-NMR (DMSO-d6)
ppm: 27.65, 28.15, and 28.38 (CH2); 113.4, 133.4, 139.8, and 154.5 (thio-
phene ring carbon atoms), 156.5 (CS) and 172.9 (CO). MS (EI+Q1MS
LMR UP LR): 224.0 (M+) 100%.
2-Arylmethylene-2,3,4,6,7,8-hexahydrothiazolo[3,2-a]
cyclopentenothieno[2,3,-d]-Pyrimidin-5H-3, 5-dione
3a–d—General Procedure
Method A
A mixture of compound 2 (2.24 g, 0.01 mol), chloroacetic acid (0.95 g,
0.01 mol), appropriate aromatic aldehyde (0.01 mol), and anhydrous
sodium acetate (0.02 mol) were stirred under reflux in glacial acetic
acid (30 mL) and acetic anhydride (15 mL) for 3 h. The reaction mixture
was cooled and poured into water (100 mL). The deposited precipitate
was filtered off and recrystallized from the appropriate solvent to yield
the title product.

Facile Syntheses of Some Thieno[2,3-d] Pyrimidine Derivatives
3069
Method B
A mixture of compound 4 (2.64 g, 0.01 mol), the appropriate aromatic
aldehyde (0.01 mol) and anhydrous sodium acetate (0.02 mol) were
stirred under reflux in glacial acetic acid (30 ml) and acetic anhydride
(15 mL) for 2 h. The reaction mixture was allowed to cool to room
temperature and poured into water (100 mL). The deposited precipitate
was filtered off and recrystallized from the appropriate solvent to yield
the title product.
2-(Phenylmethylene)-2,3,4,6,7,8-hexahydrothiazolo[3,2-a]
cyclopentenothieno[2,3-d] primidin-5H-3,5-dione (3a)
The compound was recrystallized from dimethylformamide (20 mL)
to yield the title product as light pale yellow crystals (2.85 g, 81%);
m.p. 296–298◦C; [C18H12N2S2O2] (352.3); Found C, 61.35%; H, 3.40%;
N, 7.87%. Required: C, 61.36%; H, 3.40%; N, 7.95%); IR (potassium bro-
1
mide) cm−1: 2900 (CH) and 1760, 1697 (2CO); H-NMR (CF3 COOD:
CDCl3/1:1) δ ppm: 2.55 (m, 2H, CH2), 3.04 (m, 4H, 2CH2), 7.59 (s, 1H,
CH), and 7.60–7.67 (m, 5H, phenyl protons); 13C-NMR (CF3COOD:
CDCl3/1:1) δ ppm: 28.7, 29.6 and 30.2 (CH2); 67.4 (CH); 109.2, 113.6,
113.8, 118.1, 118.4, 122.3, 122.7, 130.7, 132.3, 133.2, 133.7, 142.4,
and 143.5 (thiophene carbon atoms, pyrimidine carbon atom, thiazol
carbon atom, and phenyl carbon atoms), 173.6 and 175.2 (2CO); MS
(EI+MS/70 ev/T = 225◦C) 352 (M+) 26.41%, 323 (M-COH) 12.86%, and
133.9 (C6H5CH CS+) 100%.
2-(4-Methoxyphenylmethylene)-2,3,4,6,7,8-hexahydrothiazolo
[3,2-a] cyclopentenothieno [2,3-d]pyrimidme- 5H-3,5-dione
(3b)
The compound was recrystallized from dimethylformamide (20 mL)
to yield the title product as yellow crystals (3.17 g, 83%); m.p. 261–
262◦C; [C19H14N2S2O3] (382.5); Found: C, 59.11%; H, 4.16%; N, 6.58%.
Required: C, 59.66%; H, 3.68%; N, 7.33%); IR (potassium bromide) cm−1
:
3432 (broad OH); 2926 (CH aliphatic) and 1707, 1695 (2CO); 1H-NMR
(CF2 COOD: CDCl3/1:1) δ ppm: 2.57 (m, 2H, CH2), 3.05 (m, 4H, 2CH2),
3.96 (s, 3H, OCH3), 7.26 (d, 2H, J =13 Hz, aromatic protons), 7.61 (d,
2H, J = 13 Hz, aromatic protons), and 8.20 (s, 1H, CH, ethylenic proton);
13C-NMR (CF3COOD: CDCl3/1:1) δ ppm: 28.7, 29.5, and 30.2 (CH2);56.5
(CH3);67.6 (CH); 108.4, 113.0, 116.3, 117.5, 118.3, 122.0, 126.3, 134.8,
142.5, 142.7, 155.6, and 157.2 (thiophene ring carbon atoms and aro-
matic carbon atoms, pyrimidine ring carbon atoms, thiazol ring car-
bon atoms), and 170.8, 175.0 (2CO); MS (EI+MS/70 ev/T: 230◦C) 382

3070
A. S. Aly et al.
(M+)97.5%, 533 (M-HCO) 12.5%, 191 (M-C10H8SO2) 10.42%, and 164
(C9H8SO) 100%.
2-(4-Chlorophenylmethylene)-2,3,4,6,7,8-hexahydrothiazolo
[3,2-a]cyclopentenothieno [2,3-d] pyrimidin-5H-3,5-dione (3c)
The product was recrystallized from dimethylformamide (20 mL) to
yield the title compound as yellow crystals (2.93 g, 76%); m.p. > 300◦C;
[C18H11N2S2O2Cl] (286.9); Found: C, 56.11%; H, 2.88%; N, 7.01%. Re-
quired; C, 55.88%; H, 2.87%; N, 7.24%; IR (potassium bromide) cm−1
:
3020 (CH aryl), 293 (CH aliphatic), 1760, 1693 (2CO); 1H-NMR(DMSO-
d6) δ ppm: 2.47 (m, 2H, CH2), 2.84 (m, 4H, 2CH2), 7.61 (d, 2H, J=10 Hz
aromatic protons), 7.65 (d, 2H, J=10 Hz, aromatic protons), and 7.98
(s, 1H, ethylenic proton); MS (EI+MS/70 ev/T=250◦C) 386 (M+) 18.5%,
247 (M-HCO) 8.52%, 222 (C9H5OCl) 12.20%, and 190 (C9H5SOCI)
16.00%.
2-(4-Flurophenylmethylene)-2,3,4,6,7,8-hexahydrothiazolo
[3,2-a]cyclopentenothieno [2,3-d] pyrimidine-5H-3,5-dione (3d)
The product was recrystallized from dimethylformamide (20 mL)
to yield the title compound as yellow crystals (2.88 g, 78%), m.p. >
300◦C; [C18H11N2S2O2F] (370.8); Found: C, 58.27%; H, 2.9%7; N, 7.66%.
Required: C, 58.36%; H, 2.99%; N, 7.56%; IR (potassium bromide) cm−1
:
1
3020 (CH aryl), 2946 (CH aliphatic) and 1760, 1693 (2CO); H-NMR
(CF3COOD; CDCl3/1:1) δ ppm:2.62 (m, 2H, CH2), 3.07 (m, 4H, 2CH2),
7.27 (d, 2H, J = 10 Hz aromatiic protons), 7.57 (s, 1H, ethylenic proton),
and 8.25 (d, 2H, J = 10 Hz, aromatic protons). MS (EI+Q1MS LMR UP
LR): 370.0 (M+) 100%.
2,3,4,6,7,8-Hexahydro-5H-thiazolo[3,2-a]cyclopeiitlnothieno
[2,3-d] pyrimidin-3,5-diones (4)
A mixture of comopound 2 (2.24 g, 0.01 mol), chloroacetic acid (0.95 g,
0.01 mol) and anhydrous sodium acetate (1.64 g, 0.01 mol) was heated
gently, with stirring on a water bath (60◦C) for 2 h. The reaction mixture
was allowe to cool to room temperature and poured into water (100 mL).
The deposited precipitate was filtered off and recrystallized from
dimethylformamide (20 mL) to afford the title product as a colorless
powder (1.61 g, 61%), m.p. > 300◦C; [C11H8N2S2O2] (264.3); Found: C,
49.62; H, 3.16; N, 10.22. Required: C, 49.98; H, 3.05; N, 10.60%); IR
(potassium bromide) cm−1: 2928 (CH aliphatic), and 1668, 1665 (2CO);
1H-NMR (DMSO-d6) δ ppm: 2.35 (m, 2H, CH2), 2.80 (m, 4H, 2CH2) and

Facile Syntheses of Some Thieno[2,3-d] Pyrimidine Derivatives
3071
3.45 (s, 2H, CH2); MS (El+QlMSLMR UP LR): 264.0 (M+) 8.2%, 224.0
(Base peak) 100% and 191.0 (C2SO2).
2-(S-alkyl)-3, 5, 6, 7-tetrahydrocyclopentenothieno [2, 3-d]
pyrimidin-4(4H)-one (5a-f)—General Method
To a warmed ethanolic potassium hydroxide solution [prepared by dis-
solving potassium hydroxide (0.56 g, 0.01 mol) in ethanol (50 mL)]
was adde compound 2 (2.24 g, 0.01 mol). The heating was continued
for 30 min, the mixture was allowed to cool to room temperature, and
the proper halo compound (0.012 mol) was added. The mixture was
sirred under reflux for 5 h, then cooled to room temperature and poured
onto water (100 mL). The solid product soprecipitated was filtered off,
washed with water, dried, and recrystallized from the appropriate sol-
vent to produce 5a–f.
2-(Methylthio)-3, 5, 6, 7-tetrahydrocyclopentenothieno [2, 3-d]
pyrimidin-4(4H)-one 5a
From compound 2 (2.24 g, 0.01 mol) and metyl iodide (1.72 g, 0.012
mol). The compound was re-crystallized from dioxane (30 mL.) to
yield the title product as clorless crystals (1.57 g, 66%), m.p. 273–
75◦C, [C10H10N2S2O] (238.3); Found: C, 50. 10%; H, 3.90%; N, 11.55%.
Required C, 50.39%; H, 4.22%; N, 11.75%; IR (potassium bromide)
cm−1:3400 (broad NH), 2920 (CH alkyl) and 1680 (CO); 1H-NMR
(DMSO-d6) δ ppm (m, 2H, CH2), 2.45 (s, 3H, SCH3), 2.85 (m, 4H, 2CH2),
and 8.65 (br s, 1H, NH, D2O exchangeable); 13C-NMR (DMSO-d6) δ ppm:
22.9, 27.3, 28.6, and 28.8 (3CH2 +CH3); 116.5, 135.3, 139.3, 156.2, and
157.7 (thienopyrimidone carbon atoms) and 168.3 (CO). MS (EI-MS/70
ev/T = 230◦C):238.0 (M+) 18.72%.
2-(Ethylthio)-3, 5, 6, 7-tetrahydrocyclopentenothieno [2, 3-d]
pyrimidn-4 (4H)-one 5b
From compound 2 (2.24 g, 0.01 mol) and ethyl iodide (1.86 g,
0.012 mol). The compound was recrystallized from ethanol to yield
the title product as colorless crystals (1.70 g, 63%), m.p. 188–189◦C;
[C11H12N2S2O] (252.2); Found: C, 51.73%; H, 4.51%; N, 10.77%. Re-
quired: C, 52.35%; H, 4.79%; N, 11.10%; IR (potassium bromide) cm−1
:
1
3400 (broad NH), 2925 (CH alkyl) and 1660 (CO); H-NMR (DMSO-
d6) δ ppm: 1.40 (t, 3H, CH3), 2.45 (m, 2H, CH2), 2.90 (t, 2H, CH2),
3.05 (t, 2H, CH2), and 9.70 (br s, 1H, NH, D2O exchangeable); 13C-
NMR (DMSO-d6) δ ppm: 13.9 (CH3); 24.7 (SCH3); 27.5, 28.6, and 28.9
(CH2); 116.7, 135.6, 139.4, 154.5, and 158.7 (thienopyrimidone carbon

3072
A. S. Aly et al.
atoms), and 168.6 (CO); MS (EI-MS/70 ev/T = 230◦C):252.2 (M+)
18.72%.
2-(Aceticacidthio)-3, 5, 6, 7-tetrahydrocyclopentenothieno
[2,3-d] pyrimidn-4 (4H) one 5c
From compound 2 (2.24 g, 0.01 mol) and chloroacetic acid (1.14 g,
0.012 mol). The compound was recrystallized from dioxane (25 mL) to
yield the title product as colorless crystals (1.70 g, 66%), m.p. 242–
243◦C; [C11H10N2S2O3] (282.3); Found: C, 45.97%; H, 3.32%; N, 9.83%.
Required: C, 46.79%; H, 3.57%; N, 9.92%; IR (potassium bromide) cm−1
:
3240 (broad NH), 2925 (CH alkyl) and 1720, 1688 (2CO); 1H-NMR
(CDCl3:DMSO-d6/1:1) δ ppm: 2.45 (m, 2H, CH2), 2.85 (m, 4H, 2CH2),
3.95 (s, 2H, CH2), and 5.85 (br s, 1H, NH, D2O exchangeable); 13C-NMR
(CDCl3: DMSO-d6/1:1) δ ppm: 27.6, 28.6, 29.0, and 32.6 (CH2); 116.9,
135.7, 139.5, 154.2, and 158.1 (thienopyrimidone carbon atom), and
168.1, 169.5 (2CO); MS (EI-MS/70 ev/T = 240◦C): 282 (M+) 87% and
264 (M-18) 100%.
2-(Ethylacetatethio)-3, 5, 6, 7-tetrahydrocyclopentenothieno
[2, 3-d] primidin-4 (4H)-one (5d)
From compound 2 (2.24 g, 0.01 mol) and ethyl bromoacetate (2.00g,
0.012 mol). The compound was recrystallized from ethanol (25 mL) to
yield the titled product as colorless crystals (2.20 g, 71%), m.p. 202–
203◦C; [C13H14N2S2O3] (310.38); Found C, 49.75%; H, 4.22%; N, 9.30%;
S, 21.20%. Required: C, 50.30%; H, 4.55%; N, 9.03%; S, 20.66%; IR
(potassium bromide) cm−1: 3220 (broad NH), 2930 (CH alkyl), and 1720,
1680 (C N) and 1480 (C C); 1H-NMR (CDCI3) δ ppm: 1.40 (t, 3H, CH3),
2.45 (m, 2H, CH2), 2.90 (t, 2H, CH2), 3.05 (t, 2H, CH2), 3.25 (q, 2H, CH2),
3.55 (s, 2H, CH2), and 9.18 (br s, 1H, NH, D2O exchangeable); MS (El
+ Q1 MS LMR UP LR): 310.0 (M+) 27.12%.
2-(Phenacylthio)-3, 5, 6, 7-tetrahydrocyclopentenothieno [2,
3-d] pnmid-in-4(4H)-one (5e)
From compound 2 (2.42 g, 0.01 mol) and phenacyl bromide (2.38 g,
0.012 mol). The compound was recrystallized from dioxane (30 mL.)
to yield the title product as pale yellow crystals (2.63 g, 77%), m.p.
257–258◦C; [C17H14N2S2O2] (342.4); Found: C, 59.63%; H, 4.22%; N,
8.25%; S, 17.77%. Required: C, 59.62%; H, 4.12; N, 8.18%; S, 18.72%.
IR (potassium bromide) cm−1: 3448 (broad OH and NH), 3050 (CH aro-
1
matic), 2911 (CH alkyl) and 1680, 1670 (2CO); H-NMR (DMSO-d6)
δ ppm: 2.30 (m, 2H, CH2), 2.80 (m, 4H, 2CH2), 4.85 (s, 2H, CH2),

Facile Syntheses of Some Thieno[2,3-d] Pyrimidine Derivatives
3073
7.50–7.75 (m, 5H, phenyl protons), and 11.20 (br s, 1H, NH, D2O ex-
changeable). MS (EI+Q1MS LMR UP LR): 222.0 (M+) 100%.
2-(Acetylacetonethio)-3, 5, 6, 7-tetrahydrocyclopentenothieno
[2,3-d]-pyrimidin-4(4H)-one. (5f)
From Compound 2 (2.24 g, 0.01 mol) and chloroaceacetylacetone
(1.61 g, 0.012 mol). The compound was recrystallized from dioxane
(30 mL) to yield the title product as yellow crystals (2.58 g, 80%), m.p.
260–262◦C; [C14H14N2S2O3] (322.4); Found: C, 52.24%; H, 4.35%; N,
8.66%. Required: C, 52.15%; H, 4.37%; N, 8.69%; IR (potassium bro-
mide) cm−1: 3420 (broad NH, and OH), 2860 (CH alkyl) and 1690,
1
1590 (2CO); H-NMR (DMSO-d6) δ ppm: 2.25 (s, 6H, 2CH3), 2.38 (m,
2H, CH2), 2.85 (m, 4H, 2CH2), 7.81 (s, 1H, CH2) and 12.82 (br s,
1H, NH, D2O exchangeable); MS (EI+Q1 MS LMRUPLR): 322.1 (M+)
87.89%.
2-Hydrazino-3,5,6,7-tetrahydrocyclopentenothieno [2,3-d]
pyrimidin-4(4H)-one (6)
A mixture of compound 5a (2.38g, 0.01 mol) and hydrazine hydrate
(99–100%) (7 mL, 0.03 mol) in dioxane (20 mL) and ethanol (10 ml)
was heated under reflux for 4 h. The solid that separated upon cooling
the reaction mixture was filtered off and recrystallized from dioxane-
dimethylformamide (4:1, 25 mL) to yield the title compound as a color-
less crystals (1.44 g, 65%), m.p. > 300◦C; [C9H10N4SO](222.0); Found:
C, 48.51%; H, 4.46%; N, 24.91%. Required: C, 48.63%; H, 4.54%; N,
25.21%; IR (potassium bromide) cm−1: 3322 (NH2), 3245 (NH), 2913
1
(CH alkyl), and 1666 (CO); H-NMR (DMSO-d6) δ ppm: 2.30 (m, 2H,
CH2), 2.80 (m, 4H, 2CH2), and 8.20 (br s, 1H, NH, D2O exchangeable);
MS (EI+Q1MS LMR UP LR): 222.0 (M+) 100%.
2-Alkylthio-3-alkyl-3,5,6,7-tetrahydrocyclopentano[2,3-d]
pyrinmdin-4-one (7a,b)—General Procedure
To a warmed ethanolic sodium ethoxide solution [prepared by dissolv-
ing (0.23 g, 0.01 mol) of sodium metal in absolute ethanol (30 mL)] was
added each of compound 5a or 5b (0.01 mol), the heating was contin-
ued for 30 min, the mixture was allowed to cool to room temperature,
and the proper alkyl iodide (0.012 mol) was added. The mixture was
stirred under reflux for 3 h, cooled to room temperature, and poured into
cold water (100 mL). The solid soprecipitated was filtered off, washed

3074
A. S. Aly et al.
with water, dried and recrystallized from the appropriate solvent to
produce 7a,b.
2-Ethylthio-3-methyl-4,5,6,7-tetrahydrocyclopentenothieno
[2,3-d]pyrimidin-4-one (7a)
From compound 5b (2.52 g, 0.01 mol) and methyl iodide (1.72 g, 0.012
mol). The compound was recrystallized from ethanol (20 mL) to yield
the title product as colorless crystals (2.16 g, 81%), m.p. 197–198◦C;
[C12H14N2S2O](266.3); Found: C, 54.2%; H, 4.90%; N, 9.89%. Required:
C, 54.11%; H, 5.30%; N, 10.52%; IR (potassium bromide) cm−1: 2850
1
(CH alkyl) and 1666 (CO); H-NMR (CDCl3) δ ppm: 1.40 (t, 3H, CH3),
2.45 (m, 2H, CH3), 2.65 (s, 3H, CH3), 2.75 (t, 2H, CH2), 3.00 (t, 2H,
CH3), and 4.15 (q, 2H, CH2). MS (El + Ql MS LMR UP LR): 266 (M+)
12%.
2-Methylthio-3-ethyl-4,5,6,7-tetrahydrocyclopentenothieno
[2,3-d]pyrimidin-4-one (7b)
From compound 5a (2.38 g, 0.01 mol) and ethyl iodide (1.86 g, 0.012
mol). The compound was recrystallized from ethanol (25 mL) to yield
the title product as colorless crystals (2.05 g, 77%), m.p. 207–208◦C;
[C12H14N2S2O] (266.3); Found: C, 53.64%; H, 4.93%; N, 9.70%. Re-
quired: C, 54.2%; H, 5.30%; N, 10.52%; IR (potassium bromide) cm−1
:
1
2911 (CH alkyl) and 1677 (CO); H-NMR (CDCl3) δ ppm: 1.40 (t, 3H,
CH3), 2.45 (m, 2H, CH3), 2.60 (s, 3H, CH3), 2.90 (t, 2H, CH2), 3.05 (t,
2H, CH2), and 4.00 (q, 2H, CH2); MS (El + Q1 MS LMR UP LR): 266
(M+) 17%.
2-(Methylthio)-3,5,6,7-tetrahydrocyclopentenothieno[2,3-d]-
pyrimidin-S,S-dioxid-4(4H)-one (9)
A mixture of compound 5a (2.24 g, 0.01 mol) and hydrogen peroxide
(5 mL) in acetic acid (30 mL) was heated gently with stirring for 6 h;
the reaction mixture was allowed to cool to room temperature. The
deposited precipitate was filtered off, and recrystallized from dioxane
(25 mL) to yield the title product as a colorless crystals (1.56 g, 58%);
m.p. 284–286◦C; [C13H10N2S2O3] (270.23); Found: C, 44.12%; H, 3.66%;
N, 9.75%; S, 23.11%. Required: C, 44.43%; H, 3.73%; N, 10.3% 6; S,
23.72%; IR (potassium bromide) cm−1: 3151 (NH), 2907 (CH alkyl) and
1666 (CO); 1H-NMR (DMSO-d6) δ ppm: 2.35 (m, 2H, CH2), 2.45 (s,
3H, SCH3), 2.80 (t, 2H, CH2), 2.90 (t, 2H, CH2), and 11.80 (br s, 1H,
NH, D2O exchangeable); MS (El + Q1 MS LMR UP LR): 270.0 (M+)
12%.

Facile Syntheses of Some Thieno[2,3-d] Pyrimidine Derivatives
3075
2-(3,5-Dimethyl-1H-or(1-phenyl)pyrazol-4-ylthio)-3,5,6,7-
tetrahydrocyclopentenothieno [2,3-d] pyrimidin-4-one
(10a,b)—General Procedure
A mixture of compound 5f (3.22 g, 0.01 mol) and hydrazine hydrate
(99–100%) or phenyl hydrazine hydrochloride (0.01 mol) in dioxane (20
mL) and ethanol (10 mL) was stirred under reflux for 8 h. The reaction
mixture was allowed to cool to room temperature and then poured into
cold water (100 mL). The deposited precipitate was filtered off, dried,
and recrystallized from the appropriate solvent to produce 10a,b.
2-(3,5-Dimethyl-lH)pyrazol-4-ylthio)-3,4,5,6,7-tetrahydrocyclo-
pentanothieno[2,3-d]pyrimidin-4-one(10a)
From compound 5f (3.22 g, 0.01 mol) and hydrazine hydrate (10 mL).
The compound was recrystallized from dixoane (25 mL) to yield the
title product as light colorless crystals (2.45 g, 77%), m.p. > 300◦C;
[C14H14N4N4S2O] (318.4); Found: C, 51.89%; H, 4.13%; N, 16.82%.
Required: C, 52.81%; H, 4.43%; N, 17.60%); IR (potassium bromide)
1
cm−1: 3420 (NH), 2880 (CH alkyl), and 1660 (CO); H-NMR (CDCl3:
CF3COOD/1:2) δ ppm: 2.56 (m, 2H, CH2), 2.61 (s, 6H, 2CH3), 3.00 (m,
4H, 2CH2), and 8.85 (br s,1H,NH,D2O exchangeable); 13C-NMR (CDCl3:
CF3COOD/1:2) δ ppm: 10.8 and 10.9 (CH3); 29.0, 29.6, and 30.5 (CH2),
113.5, 118.0, 118.7, 122.6, 141.5, 144.5, 154.1, and 154.4 (thienopyrim-
idone carbon atoms and pyrazol ring carbon atoms), and 164.6 (CO);
MS (EI-MS/70 ev/T = 265◦C): 318 (M+) 36.29%.
2-(3,5-Dimethyl-1-phenylpyrazol-4-ylthio)-3,4,5,6,7-
tetrahydrocyclopenteno[2,3-d]pyrimidin-4-one(10b)
From compound 5f (3.22 g, 0.01 mol) and phenyl hydrazine hy-
drochloride (1.45 g, 0.01 mol). The compound was recrystallized from
dioxane (30 mL) to yield the title product as light pale yellow crys-
tals (2.60 g, 66%); m.p. 276–277◦C;[C20H18N4S2O] (394.5); Found: C,
60.81%; H, 4.43%; N, 13.87%. Required: C, 60.88%; H, 4.50%; N,
14.20%); IR (potassium bromide) cm−1: 3448 (broad NH), 3050 (CH
aromatic), 2826 (CH alkyl) and 1670 (CO); 1H-NMR (DMSO-d6) δ ppm:
2.20 (s, 3H,CH3), 2.35 (s, 3H, CH3), 2.47 (m, 2H, CH2), 2.85 (m, 4H,
2CH2), 7.43–7.53 (m, 5H, phenyl protons), and 12.30 (br s, 1H, NH,
D2O exchangeable); 13C-NMR (DMSO-d6) δ ppm: 11.4 and 11.8 (CH3);
27.4, 28.6, and 28.9 (CH2); 101.2, 117.1, 124.4,127.8, 129.2, 135.9, 139.4,
139.5, 144.7, 152.1, 152.8, 154.6, and 157.1 (Thienopyrimidone carbon
atoms, pyrazol ring carbon atoms, and phenyl carbon atoms) and 168.8
(CO); MS (EI-MS/70 ev/T = 210◦C): 394 (M+) 52.51%.

3076
A. S. Aly et al.
2-Acetyl-3-methylthiazolo [3,2-a]-5,6,7,8-tetrahydrocyclopent-
enothieno [2,3-d] pyrimidin-5-one (11)
A solution of compound 5f (3.22 g, 0.01 mol) in a mixture of acetic an-
hydridepyridine (20 mL: 10 mL) was stirred under reflux for 3 h. The
reaction mixture was allowed to cool to room temperature, then the de-
posited precipitate was filtered off, dried, and recrystallized from diox-
ane (30 ml) to yield the title product as a light yellow crystals (2.47 g,
81%), m.p. 206–208◦C; [C14H12N2S2O2] (304.3); Found: C, 55.25%; H,
3.82%; N, 9.29%. Required: C, 55.2%5; H, 3.97%; N, 9.21%); IR (potas-
1
sium bromide) cm−1: 2962 (CH alkyl) and 1698, 1660 (2CO); H-NMR
(DMSO-d6) δ ppm:2.30 (m, 2H, CH2), 2.45 (s, 3H, CH3), 2.70 (m, 4H,
2CH2), and 3.00 (s, 3H, CH3); 13C-NMR (DMSO-d6) δ ppm: 16.5 and
27.6 (CH3), 29.1, 29.3, and 30.6 (CH2), 114.9, 121.2, 136.2, 139.9, 142.4,
156.6, and 157.3 (thiazolothienoprimidone carbon atoms) and 167.4,
190.5 (CO); MS (EI-MS/70 ev/T =160◦C): 304 (M+) 100%.
2-(Acetoxime)-3-methylthiazolo [3,2-a]-5,6,7,8-tetrahydro
cyclo-pentenothieno [2,3-d] pyrimidin-5-one (12)
A mixture of compound 11 (3.04 g, 0.01 mol) and hydroxylamine hy-
drochloride (0.70 g, 0.01 mol) in dioxane (30 mL) and catalytic amount of
piperidine was added. The reaction mixture was stirred under reflux for
8 h, and then it was allowed to cool to room temperature and poured into
water (100 mL). The deposited precipitate was filtered off, dried, and
recrystallized from dimethylformamide (25 mL) to yield the title prod-
uct as yellow crystals (1.94 g, 61%), m.p. 237–238◦C; [C14H13N3S2O2]
(319.38); found: C, 52.70; H, 3.77; N, 12.60. Required: C, 52.65; H, 4.10;
N, 13.16%); IR (potassium bromide) cm−1: 3450 (broad OH and NH),
1
2880 (CH alkyl) and 1680 (CO); H-NMR (DMSO-d6) δ ppm: 2.35 (m,
2H, CH2), 2.40 (s, 3H, CH3), 2.8 (s, 3H, CH3), and 2.85 (m,4H,2CH2);
MS (EI-Q1 MS LMR UP LR): 319 (M+) 100%; 360 (m/z) 100%; 318 (m/z)
70% and 302 (m/z) 80%.
2-(Acetothiosemicarbazone)-3-methylthiazolo [3, 2-a]-5, 6, 7,
8-tetrahydrocyclopenteno-thieno [2,3-d] pyrimidin-4-one (13)
A mixture of compound 11 (3.04 g, 0.01 mol) and thiosemicarbazide
(0.91 g, 0.01 mol) in dioxane (30 ml) and catalytic amount of piperidine
was added. The reaction mixture was stirred under reflux for 8 h, and
then it was allowed to cool to room temperature and poured into water
(100 mL). The deposited precipitate was filtered off, dried, and recrys-
tallized from dimethylformamide (25 ml) to yield the title product as

Facile Syntheses of Some Thieno[2,3-d] Pyrimidine Derivatives
3077
yellow crystals (2.72 g, 72%), m.p. 244–246◦C; [C15H15N5S3O] (377.5);
Found: C, 46.80; H, 3.45; N, 18.61. Required: C, 47.72; H, 4.01; N,
18.55%); IR (potassium bromide) cm−1: 3450 (NH2), 3150 (NH), 2925
1
(CH alkyl), and 1689 (CO); H-NMR (DMSO-d6) δ ppm: 2.30 (s, 3H,
CH3), 2.40 (m, 2H, CH2), 2.85 (s, 3H, CH3), 2.95 (m, 4H, 2CH2), 7.45
(br s, 2H, NH2, D2O exchangeable), and 10.65 (br s, 1H, NH, D2O ex-
changeable); MS (EI+Q1 MS LMR UP LR) 377.0 (M+) 11.75%.
2-Cinnamoyl (derivatives)-3-methylthiazolo [3,2-a]-5,6,7,8-
tetrahydrocyclopenteno-thieno [2, 3-d] pyrimidin-5-one
(14a–c)—General Procedure
A mixture of compound 11 (3.22 g, 0.01 mol), the proper aromatic
aldehyde (0.01 mol), and a catalytic amount of piperidine was heated
at 170–180◦C in a test tube for 3 h. The product was solidified by
cooling and addition of methanol (50 mL). The precipitate so formed
was collected by filtration and recrystallized from the proper solvent to
produce 14a–c.
2-Cinnamoyl-3-methyl-thiazolo [3,2-a]-5,6,7,8-
tetrahydrocyclo-pentenothieno [2,3-d] pyrimidin-5-one (14a)
From compound 11 (3.22 g, 0.01 mol) and benzaldehyde (1.06 g, 0.01
mol). The compound was recrystallized from dioxane (30 mL) to yield
the title compound as yellow crystals (2.47 g, 63%), mp. 235–236◦C;
[C21H16N2S2O2](392.48); Found: C, 64.7; H, 3.71; N, 6.77. Required:
C, 64.26; H, 4.11; N, 7.14%); IR (potassium bromide) cm−1: 3020 (CH
1
aromatic), 2920 (CH alkyl) and 1693, 1680 (2CO); H-NMR (CDCl3) δ
ppm: 2.45 (m,2H,CH2), 2.95 (t, 2H, CH2), 3.10 (t, 2H, CH2), 3.15 (s,
3H, CH3), 7.05 (d, 1H, J = 10 Hz, ethylenic proton), 7.45–7.80 (m, 5H,
phenyl protons) and 7.85 (d, 1H, J = 10 Hz, ethylenic proton). MS/70
ev/T = 160◦C): 304 (M+) 100%.
2-(p-Methoxycinnamoyl)-3-methylthiazolo
[3,2-a]-5,6,7,8-tetrahydrocyclopenteno-thieno [2,3-d]
pyrimidin-5-one (14b)
From compound 11 (3.22 g, 0.01 mol) and 4-methoxybenzaldehyde
(1.36 g, 0.01 mol). The compound was recrystallized from dioxane
(30 mL) to yield the title product as yellow crystals (2.58 g, 61%), m.p.
246–248◦C; [C22H18N2S2O2](422.5); Found: C, 62.31; H, 3.91; N, 6.50%.
Required: C, 62.54; H, 4.29; N, 6.63%); IR (potassium bromide) cm−1
:
3025 (CH aromatic), 2929 (CH alkyl), 1700, 1695 (2CO), 1519 (C N),
and 14,900 (C C); 1H-NMR (CDCl3) δ ppm: 2.45 (m, 2H, CH2), 2.90 (t,
2H, CH2), 3.05 (t, 2H, CH3), 3.2 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 6.90
(d, 1H, J = 10 Hz, ethylene proton), 7.00–7.60 (m, 4H, phenyl protons),

3078
A. S. Aly et al.
and 7–80 (d, 1H, J = 10HZ, ethylenic proton). MS/70 ev/T = 160◦C): 422
(M+) 100%.
2-(P-Chlorocmnamoyl)-3-methylthiazolo
[3,2-a]-5,6,7,8tetrahydrocyclopenteno-thieno [2,3-d]
pyrimidin-5-one (14c)
From compound 11 (3.22 g, 0.01 mol) and 4-chlorobenzaldehyde
(1.41 g, 0.01 mol). The compound was re crystallized from dioxane
(30 mL) to yield the title product as yellow crystals (2.82 g, 66%), m.p.
272–275◦C, [C21H15N2S2O2Cl](426.92); Found: C, 59.10; H, 3.7; N, 6.42.
Required: C, 59.07; H, 3.54; N, 6.56%; IR (potassium bromide) cm−1
:
1
3015 (CH aromatic), 2929 (CH alkyl) and 1700, 1689 (2CO); H-NMR
(CDCl3) δ ppm: 2.45 (m, 2H, CH2), 2.85 (t, 2H, CH2), 3.00 (t, 2H, CH2),
3.25 (s, 3H, CH3), 6.85 (d, 1H, J = 10HZ, ethylenic proton), 7.00–7.65
(m, 4H, phenyl protons), and 7.85 (d, 1H, J = 10HZ, ethylenic proton).
MS/70 ev/T = 160◦C): 426.0 (M+) 100%.
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