Synthesis and reactions of novel thienopyrimidine and thiazolothienopyrimidine derivatives

Article abstract of DOI:10.1080/10426500701407714

In a one-pot reaction, 2-arylidine-6,7,8,9-tetrahydrohexenothieno[2,3-d] pyrimi-dine-3(3H),5(5H)-diones 2a, b were prepared by the reaction of a ternary mixture of 2-thioxo-5,6,7,8-tetrahydrohexenothieno[2,3-d]pyrimidin-4(4H)-one1(1) , chloroacetic acid, and a proper aldehyde. Compound 2a react with hydroxyl amine hydrochloride to give corresponding oxime derivative 4. Reaction of 1 with 3-chloropent-2, 4-dione in ethanolic sodium hydroxide solution yielded S-acetyl acetone derivative 5b. The latter compound reacted with hydrazines affording the 2-pyrazolthio 6. Compound 5b reacted with urea and thiourea to give 7a, b. Also, compound 5b underwent cyclization on boiling with acetic anhydride/pyridine mixture to yield thiazolopyrimidine derivative 8. Ketone compound 8 formed an oxime 9. Moreover, condensation of 8 with aromatic aldehyde furnished the derivative 11.

Full text of DOI:10.1080/10426500701407714

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Phosphorus, Sulfur, and Silicon
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Synthesis and Reactions of
Novel Thienopyrimidine and
Thiazolothienopyrimidine
Derivatives
Kh. M. Abu-Zied a
a National Research Center, Photochemistry
Department (Heterocyclic Unit) , Dokki, Cairo, Egypt
Published online: 16 Jul 2007.
To cite this article: Kh. M. Abu-Zied (2007) Synthesis and Reactions of Novel
Thienopyrimidine and Thiazolothienopyrimidine Derivatives, Phosphorus,
Sulfur, and Silicon and the Related Elements, 182:9, 2179-2191, DOI:
10.1080/10426500701407714
To link to this article: http://dx.doi.org/10.1080/10426500701407714
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Phosphorus, Sulfur, and Silicon, 182:2179–2191, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701407714
Synthesis and Reactions of Novel Thienopyrimidine
and Thiazolothienopyrimidine Derivatives
Kh. M. Abu-Zied
National Research Center, Photochemistry Department
(Heterocyclic Unit), Dokki, Cairo, Egypt
In a one-pot reaction, 2-arylidine-6,7,8,9-tetrahydrohexenothieno[2,3-d]pyrimi-
dine-3(3H),5(5H)-diones 2a,b were prepared by the reaction of
a ternary
mixture of 2-thioxo-5,6,7,8-tetrahydrohexenothieno[2,3-d]pyrimidin-4(4H)-one1 (1),
chloroacetic acid, and a proper aldehyde. Compound 2a react with hydroxyl amine
hydrochloride to give corresponding oxime derivative 4. Reaction of 1 with 3-
chloropent-2, 4-dione in ethanolic sodium hydroxide solution yielded S-acetyl ace-
tone derivative 5b. The latter compound reacted with hydrazines affording the 2-
pyrazolthio 6. Compound 5b reacted with urea and thiourea to give 7a, b. Also, com-
pound 5b underwent cyclization on boiling with acetic anhydride/pyridine mixture
to yield thiazolopyrimidine derivative 8. Ketone compound 8 formed an oxime 9.
Moreover, condensation of 8 with aromatic aldehyde furnished the derivative 11.
Keywords 1H-NMR; Mass spectra; pyrimidine; pyrazolothienopyrimidine
DISCUSSION
Our interest in thieno [2, 3-d] pyrimidine synthesis emerges from the
numerous reports on their diverse biological activity.2−7
A part of our program is the synthesis of various pyrimidines and
fused pyrimidines, such as thiazolothienopyrimidine and pyrazoloth-
ienopyrimidine derivatives.
Upon heating under reflux a mixture of 2-thioxo-5, 6,7,8-tetrahydr-
ohexenothie-no[2,3-d]pyrimidin-4(4H)-one 1, chloroacetic acid and
aldehyde in acetic acid and acetic anhydride in presence of anhy-
drous sodium acetate, heterocycles 2a,b were obtained in a good yields
scheme 1.
The structure assignment is based on an independent preparation
of 2a,b by condensation of 3 with each of p-chloro benzaldehyde and
Received December 21, 2006; accepted April 2, 2007.
Address correspondence to Khadiga Shaheen, National Research Center, Pho-
tochemistry Department, Heterocyclic Unit, Al-Tahrire St., Dokki, Cairo, Egypt.
E-mail:khashaheen@hotmail.com
2179

2180
Kh. M. Abu-Zied
SCHEME 1
p-methoxy benzaldehyde in acetic acid in the presence of anhydrous
sodium acetate.
Compound 2a react with hydroxyl amine hydrochlorid to give corre-
sponding oxime derivative 4.
Alkylations of compound 1 in ethanolic potassium hydroxide solu-
tion with alkyl halide or choloro compound yielded alkylthio derivatives
5a–c.
Compound 5b, as a typical 1, 3-diketones, reacted with hydrazine hy-
drate and phenyl hydrazine to give the corresponding 2-(3, 5-dimethyl-
1-pheny-1H-pyrazol-4-ylthio) derivatives 6a, b, respectively.

Thieno- and Thiazolothieno-Pyrimidine Derivatives
2181
Also, compound 5b was reacted with urea and thiourea to give 7a, b
derivatives, respectively.
Compound 5b underwent cyclization on boiling with acetic anhy-
dride/pyridine mixture to yield thiazolopyrimidine derivative 8.
Ketone compound 8 formed an oxime 9 and thiosemicarbazide 10.
Also, condensation of 7 with aldehydes gave the derivatives 11a, b. The
IR spectrum of 11a displayed two carbonyl absorption bands around
1734 and 1690 cm−1
.

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Kh. M. Abu-Zied
The 2-alkylthio derivatives 5a, c underwent further alkylations on
treatment with alkyl iodide in an ethanolic potassium ethoxide solution,
the N-3 alkylated products 12. Scheme 2.
SCHEME 2
EXPERIMENTAL
Solid compounds were recrystallized to constant melting points and
dried under 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 Mi-
croanalytical unit, National Research Centre and Faculty of Science,
Cairo University. IR spectra were carried out on FT/IR 300 E Jasco
using KBr discs. 1H-NMR spectra were measured in DMSO or CDCl3,

Thieno- and Thiazolothieno-Pyrimidine Derivatives
2183
using Joel Ex. 270 NMR spectrometer. Signal was measured with refer-
ence to TMS as an internal standard. The Mass spectra were recorded
on Finnigan 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.
2-Arylmethylene-6,7,8,9-tetrahydrothiazolo[3,2-a]-
cyclohexenothieno [2,3,-d]pyrimidin-(5H)-3,5-dione
2a,b—General Procedure
Method (A)
A mixture of compound 1 (2.38 g, 0.01 mol), chloroacetic acid
(0.95 g, 0.01 mol), appropriate aromatic aldehyde (0.01 mol), and an-
hydrous sodium acetate (0.02 mol) was 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 pre-
cipitate was filtered-off and recrystallized from appropriate solvent to
yield the title product.
Method (B)
A mixture of compound 3 (2.78 g, 0.01 mol), the appropriate aro-
matic aldehyde (0.01 mol) and anhydrous sodium acetate (0.02 mol)
was stirred under reflux in glacial acetic acid (30 ml) and acetic anhy-
dride (15 ml) for 2 h. The reaction mixture was allowed to cool to room
temperature, poured into water (100 ml). The deposited precipitate was
filtered off, dried, and recrystallized from appropriate solvent to yield
the title product.
2-(p-Chlorophenylmethylene)-4,6,7,8,9-hexahydrothiazolo
[3,2-a] cyclohexenothieno[2,3-d] pyrimidin-(5H)-3,5-dione 2a
A mixture of compound 1 and p-chlorobenzaldehyde (1.06 g, 0.01
mol).The product was recrystallized from dimethylformamide (25 ml)
to yield the title product as yellow crystals (2.63 g, 72%); m.p.
298–300◦C. [C19H13N2S2O2Cl] (400.3); Required: C, 56.92%; H, 3.26%;
N, 6.98%; S, 15.99%. Found C, 56.85%; H, 3.45%; N, 6.87; S, 15.76%. IR
(KBr) cm−: 1 3028 (CH), 2900 (CH alkyl) and 1760, 1710 (2CO)1H-NMR
(CF3 COOD: CDCl3/1:1) δ ppm. 1.85 (m, 4H, 2CH2), 2.75 (t, 2H, 2CH2),
2.95 (t, 2H, 2CH2), 7.50 (d, 2H, J = 13Hz, phenyl protons), 7.75 (d,
2H, J = 13Hz, phenyl protons) and 8.10 (s, 1H, ethylenic proton).13C-
NMR(CF3COOD: CDCl3/1:1) δ ppm: 26.38, 28. 77, 30.08, and 32.40
(4CH2); 68.00 (CH); 113.00, 115.00, 116.80, 119.44, 125.11, 126.87,
129.00, 130.10, 131.36, 134.60, 143.15, and 144.00 (thiophene carbon
atoms, pyrimidine carbon atom, thiazol carbon atom, and phenyl carbon

2184
Kh. M. Abu-Zied
atoms), 170.77 and 173.80 (2CO). MS (EI + Q1MS LMR UP LR): 400.3
(M+) 100%.
2-(4-Methoxyphenylmethylene)-6,7,8,9-hexahydrothiazolo[3,
2-a] cyclohexenothie-no[2,3-d] pyrimidin-(5H)-3,5-dione 2b
A mixture of compound 1 and 4-methoxy benzaldehyde (1.36 g,
0.01 mol). The compound was recrystallized from dimethylformamide
(30 ml) to yield the title product as yellow needles crystals (3.17 g,
77%); m.p. 287–389◦C.[C20H16N2S2O3](396.49). Required: C, 60.58%;
H, 4.06%; N, 7.06%. Found: C, 60.51%; H, 3.66%; N, 6.79%. IR (KBr)
cm−: 1 3028 (CH), 2930 (CH) and 1747, 1695 (2CO).1H-NMR (CF3 COOD:
CDCl3/1:1) δ ppm: 1.70 (m, 4H, 2CH2), 3.05 (m, 4H, 2CH2), 3.96 (s,
3H, OCH3), 7.26 (d, 2H, J = 13Hz, aromatic protons), 7.61 (d, 2H, J =
13Hz, aromatic protons), and 8.20 (s, 1H, CH, ethylenic proton).13C-
NMR(CF3COOD: CDCl3/1:1) δ ppm:28.70, 29.50, 29.80, and 30.20
(CH2); 56.50 (CH3); 67.60 (CH); 108.40, 113.00, 133.80, 116.30, 117.50,
118.30, 122.00, 126.30, 134.80, 142.00, 142.50, 142.70, 155.60, and
157.20 (thiophene ring carbon atoms, pyrimidine ring carbon atom, thi-
azol ring carbon atom, and aromatic carbon atoms) and 170.8, 175.0
(2CO). MS (EI+MS/70 ev/T: 230◦C): 396(M+) 97.5%, 367 (M-HCO)
12.5%, 205 (M-C10H8SO2) 10.42% and 160 (C9H8CO) 100%.
2,3,4,6,7,8-Hexahydro-5H-thiazolo[3,2-a]cyclohexenothieno-
[2,3-d]pyrimidin-3,5-diones 3
A mixture of compound 1 (2.38 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 mix-
ture was allowed 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. [C12H10N2S2O2] (278.35). Required:
C, 51.78%; H, 3.62%; N, 10.08%. Found: C, 51.66%; H, 3.53%; N, 10.22%.
IR (KBr) cm1: 2930 (CH) and 1686, 1700 (2CO).1H-NMR (DMSO-d6)) δ
ppm: 1.70 (m, 4H, 2CH2), 2.65 (t, 2H, CH2) 2.80 (t, 2H, CH2), and 3.45
(s, 2H, CH2). 13C- NMR (DMSO-d6)δ ppm: 24.50, 25.00, 26.60, 27.20
and 28.80 (CH2); 116.5, 135.3, 139.3, 156.2, and 157.7 (Thienopyrimi-
done carbon atoms) and 164.30, 168.03 (2CO). MS (EI + Q1MS LMR
UP LR): 278(M+) (Base peak) 100%.
2-Phenylmethylene-3-oxime-2,3,5,6,7,8-
hexahydrocyclohexenothieno[2,3-d] pyrim-idine-(4H)-4-one 4
A mixture of compound 2a (3.81 g, 0.01 mol), hydroxylamine hy-
drochloride (0.70 g, 0.01 mol), and anhydrous sodium acetate (1.64 g,

Thieno- and Thiazolothieno-Pyrimidine Derivatives
2185
0.02 mol) was stirred under reflux in glacial acetic acid (30 ml) for
8 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 dioxane/dimethyl formamide (20/5 ml) to yield
the title product as colorless powder (2.19 g, 57%), m.p. 297–298◦C.
[C19H15N3S2O2] (381.48). Required: C, 59.82%; H, 3.96%; N, 11.01%;
Found: C, 59.71%; H, 3.67%; N, 10.81%; IR (K.Br) cm−1:3433 (broad
NH), 3038 (CH), 2928 (CH alkyl) and 1696 (CO).1H-NMR (DMSO-d6))
δ ppm: 1.77 (m, 4H, 2CH2), 2.68 (t, 2H, CH2) 2.83 (t, 2H, CH2), 3.87
(br s, 1H,OH, D2O exchangeable), 7.60–7.75 (m, 5H, phenyl protons),
and 8.01 (s, 1H, CH, ethylenic protons). MS (EI + Q1MS LMR UP LR):
381.4 (M+) 100%.
2-(S-Alkyl)-3,4,5,6,7,8-hexahydrocyclohexenothieno[2,3-
d]pyrimidin-4-one 5a–c—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
added compound 1 (2.38 g, 0.01 mol), the heating was continued for
30 min, and the mixture was allowed to cool to room temperature, and
the proper halo-compound (0.012 mol) was added. The mixture was
stirred under reflux for 5 h, then cooled to room temperature and poured
into water (100 ml). The solid product so-precipitated was filtered-off,
washed with water, dried, and recrystallized from appropriate solvent
to produce 5a–c.
2-(Methylthio)-3,4,5,6,7,8-hexahydrocyclohexenothieno-
[2,3-d]pyrimidin-4-one 5a
From compound 1 (2.38 g, 0.01 mol) and methyl iodide (1.82 g,
0.012 mol). The compound was recrystallized from dioxane (35 ml)
to yield the title product as a colorless crystals (1.80 g, 71%), m.p.
298–302◦C. [C11H12N2S2O] (252.35). Required; C, 52.35%; H, 4.79%; N,
11.09%; S, 25.41%. Found: C, 51.73%; H, 4.51%; N, 10.77; S, 25.11%. IR
(KBr) cm−1:3400 (broad NH), 2920 (CH alkyl) and 1680 (CO).1H-NMR
(DMSO-d6)) δ ppm: 2.35 (m, 4H, 2CH2), 2.45 (s, 3H, SCH3), 2.85 (m, 4H,
2CH2), and 11.25 (br. s, 1H, NH, D2O exchangeable). MS (EI-MS/70 ev/T
= 230◦C):252(M+) 100%.
2-(Acetylacetonethio)-3,4,5,6,7,8-
hexahydrocyclohexenothieno[2,3-d]pyrimidin-4-one 5b
From compound 1 (2.38 g, 0.01 mole) and chloroacetylacetone
(1.61 g, 0.012 mol). The compound was recrystallized from dioxane
(30 ml) to yield the title product as yellow crystals (2.72 g, 81%), m.p.

2186
Kh. M. Abu-Zied
298–300◦C. [C15H16N2S2O3] (336.44). Required: C, 53.55%; H, 4.79%;
N, 8.33%; S, 19.06%. Found: C, 53.11%; H, 4.37%; N, 7.86%; S, 18.31%.
IR (KBr) cm−1:3415 (broad NH and OH), 2930 (CH alkyl) and 1700,
1668 (CO).1H-NMR (DMSO-d6)δ ppm: 1.78 (m, 4H, 2CH2), 2.42 (s, 6H,
2CH3), 2.85 (t, 2H, CH2), 2.93 (t, 2H, CH2), 5.61 (s, 1H, CH), and
11.88 (br s, 1H, NH, D2O exchangeable).13C-NMR (DMSO-d6)δ ppm:
13.90, 16.34, 18.55, 22.48, 26.06, and 38.86 (sp2 carbon atoms), 118.70,
128.60, 136.44, 149.95, and 154.39 (Thienopyrimidone carbon atoms)
and 158.44 and 168.6 (CO). MS (EI-MS/70 ev/T = 230◦C): 336.4(M+)
87.89%.
2-(Ethylthio)-3,4,5,6,7,8-hexahydrocyclohexenothieno-
[2,3-d]pyrimidin-4-one 5c
From compound 1 (2.38 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 a colorless crystals (1.70 g, 63%), m.p. 188–189◦C.
[C12H14N2S2O] (266.38). Required: C, 52.35%; H, 4.79%; N, 11.10%.
Found: C, 51.73%; H, 4.51%; N, 10.77%. IR (KBr) cm−1: 3400 (broad NH),
2925 (CH alkyl) and 1660 (CO).1H-NMR (DMSO-d6)) δ ppm: 1.40 (t, 3H,
CH3), 2.45 (m, 4H, 2CH2), 2.76 (t, 2H, CH2), 2.90 (t, 2H, CH2), 3.05 (q,
2H, CH2), and 9.70 (br s, 1H, NH, D2Oexchangeable). MS (EI+Q1 MS
LMR UPLR):266 (M+) 100%.
2-(3, 5-Dimethyl-1H-or(1-phenyl)pyrazol-4-ylthio)-3,4,5,6,7,8-
hexahydrocyclohex-enothieno [2, 3-d] pyrimidin-4-one
6a,b—General Procedure
A mixture of compound 5b (3.36 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 6 h. The reac-
tion mixture was allowed to cool to room temperature and then poured
into cold water (100 ml). The deposited precipitate was collected upon
filtration and recrystallized from appropriate solvent to produce 6a, b.
2-(3,5-Dimethyl-1H-pyrazol-4-ylthio)-3,4,5,6,7,8-
hexahydrocyclohexenothieno[2,3-d] pyrimidin-4-one 6a
From compound 5b (3.36 g, 0.01 mol) and hydrazine hydrate
(12 ml). The compound was recrystallized from dioxane (35 ml) to
yield the title product as yellow crystals (2.25 g, 68%), m.p. 300–302◦C.
[C15H16N4S2O] (332.46) Required: C, 54.19%; H, 4.84%; N, 16.85%.
Found: C, 53.55%; H, 4.61%; N, 16.64%. IR (KBr) cm−1:3420 (NH),
2880 (CH alkyl) and 1660 (CO).1H-NMR (DMSO-d6)δ ppm: 1.76 (m,
4H, 2CH2), 2.60 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.73 (t, 2H, 2CH2), 2.88

Thieno- and Thiazolothieno-Pyrimidine Derivatives
2187
(t, 2H, CH2), and 9.05 (br s, 1H, NH, D2O exchangeable).MS (EI+Q1
MS LMR UP LR): 332.4 (M+) 86.70%.
2-(3,5-Dimethyl-1-phenylpyrazol-4-ylthio)-3,4,5,6,7,8-
hexahydrocyclohexeno[2,3-d] pyrimidin-4-one 6b
From compound 5b (3.36 g, 0.01 mol) and phenyl hydrazine hy-
drochloride (1.51 g, 0.01 mol). The compound was recrystallized from
dioxane/dimethyl formamide (30 ml/5 ml) to yield the title product as
yellow crystals (2.89 g, 71%); m.p. 283–285◦C. [C21H20N4S2O] (408.55).
Required: C, 61.73%; H, 4.93%; N, 13.71%. Found: C, 61.53%; H, 4.55%;
N, 13.45%. IR (KBr) cm−1:3443 (broad NH), 3043 (CH), 2926 (CH
alkyl), and 1670 (CO).1H-NMR (DMSO-d6)δ ppm: 1.74 (m, 4H, 2CH2),
2.15 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.77 (t, 2H, CH2), 2.90 (t, 2H,
CH2), 7.40–7.55 (m, 5H, phenyl protons), and 11.33 (br s , 1H , NH ,
D2O exchangeable).13C-NMR (DMSO-d6)δ ppm: 16.40 and 18.06 (CH3);
26.77, 27.4, 28.6 and 28.9 (CH2); 104.02, 116.11, 126.00, 127.18, 130.02,
134.49, 138.84, 140.05, 144.37, 152.81, 153.07, 155.16, and 157.21
(thienopyrimidone carbon atoms, pyrazol ring carbon atoms and phenyl
carbon atoms) and 166.70 (CO).MS (EI+Q1 MS LMR UP LR): 408.5
(M+) 91.63%.
2-(4,6-Dimethyl-2-oxo-our(2-thioxo)-1,2-dihydropyrimidin-5-
ylthio)-3,4,5,6,7,8-exahydrocyclohexenothieno[2,3-d]
pyrimidin-4-one 7a,b—General Procedure
A mixture of compound 5b (3.36 g, 0.01 mol) and urea (0.48 g, 0.01
mol) or thiourea (0.76 g,0.01 mol) was stirred under reflux in dioxane
(30 ml ) in the presence of a catalytic amount of piperidine for 8 h .The re-
action mixture was allowed to cool to room temperature and poured into
water (100 ml). The formed precipitate was filtered-off, washed withed
water, and recrystallized from suitable solvent to give compounds 7a,
b in a good yield.
2-(4,6-Dimethyl-2-oxo-1,2-dihydropyrimidin-5-ylthio)-
3,4,5,6,7,8-hexahydrocyclo-hexenothieno [2, 3-d]
pyrimidin-4-one 7a
From compound 5b (3.36 g, 0.01 mol) and urea (0.48 g, 0.01 mol).The
product was recrystallized from dioxane (30 ml) to yield 7a as yellow
powder (2.40 g, 66%), m.p. 271–273◦C. [C16H16N4S2O2] (360.47). Re-
quired: C, 53.31%; H, 4.47%; N, 15.54%. Found: C, 53.01%; H, 4.28%;
N, 14.88%.IR (K.Br) cm−1:3450 (broad NH), 2928 (CH alkyl) and 1660,
1666 (2CO).1H-NMR (DMSO-d6)δ ppm: 1.75 (m, 4H, 2CH2), 2.15 (s, 3H,
CH3), 2.30 (s, 3H, CH3), 2.75 (t, 2H, CH2), 2.83 (t, 2H, CH2), 9.35 (br s,

2188
Kh. M. Abu-Zied
1H, NH, D2O exchangeable), and 11.02 (br s, 1H, NH, D2O exchange-
able). MS (EI+Q1 MS LMR UP LR): 360.4 (M+) 100%.
2-(4,6-Dimethyl-2-thioxo-1,2-dihydropyrimidin-5-ylthio)-
3,4,5,6,7,8-hexahydrocycl-ohexenothieno[2,3-d]
pyrimidin-4-one 7b
From compound 5b (3.36 g, 0.01 mol) and thiourea (0.48 g, 0.01
mol).The product was recrystallized from dioxane (30 ml) to yield 7b as
yellow crystal (2.50 g, 67%), m.p. 278–280◦C. [C16H16N4S3O] (376.54).
Required: C, 51.03%; H, 4.28%; N, 14.88%. Found: C, 50.61%; H, 3.55%;
N, 14.54%.IR (KBr) cm−1:3443 (broad NH), 2930 (CH alkyl) and 1668
(CO).1H-NMR (DMSO-d6)δ ppm: 1.70 (m, 4H, 2CH2), 2.08 (s, 3H, CH3),
2.33 (s, 3H, CH3), 2.71 (t, 2H, CH2), 2.85 (t, 2H, CH2), 8.55 (br s, 1H,
NH, D2O exchangeable), and10.65 (br s, 1H, NH, D2O exchangeable).
MS (EI+Q1 MS LMR UP LR): 376.5 (M+) 100%.
2-Acetyl-3-methylthiazolo [3‘, 2‘-a]-5,6,7,8-
tetrahydrocyclohexenothieno[2,3-d] pyri-imidin-5-one 8
A solution of compound 5b (3.36 g, 0.01 mol) in a mixture of acetic
anhydride-pyridine (20 ml: 10 ml) was stirred under reflux for 6 h.
The reaction mixture was allowed to cool to room temperature, then
the deposited precipitate was filtered-off, dried, and recrystallized from
dioxane (30 ml) to yield the title product as a light yellow crystals (2.48,
77%), m.p. 211–213◦C. [C15H14N2S2O2] (318.42). Require: C, 56.34%;
H, 4.42%; N, 9.21%. Found: C, 55.57%; H, 3.89%; N, 8.81%. IR (KBr)
cm−1:2944 (CH alkyl) and 1700, 1666 (2CO).1H-NMR (DMSO-d6)δ ppm:
1.73 (m, 4H, 2CH2), 2.56 (s, 3H, CH3), 2.70 (t, 2H, CH2), 2.80 (t, 2H,
CH2), and 3.06 (s, 3H, CH3).13C-NMR (DMSO-d6)δ ppm: 18.03 and 26.90
(CH3), 28.90, 30.03, 30.17, and 30.67 (CH2), 113.09, 121.42, 137.11,
139.76, 142.4, 156.60, and 156.86 (Thiazolothienopyrimidone carbon
atoms) and 170.00, 185.45 (2CO). MS (EI+Q11.33 1 MS LMR UP LR):
318.4(M+) 100%.
2-(Acetoxime)-3-methylthiazolo[3‘,2‘-a]-6,7,8,9-
tetrahydrocyclohexenothieno[2,3-d]- pyrimidin-(5H)-5-one 9
A mixture of compound 8 (3. 18 g, 0.01 mol) and hydroxylamine hy-
drochloride (0.70 g, 0.01 mol) in dioxane (30 ml) and a catalytic amount
of pipridine 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 collected upon filtra-
tion and recrystallized from dioxane/dimethylformamide (20 ml/10 ml)
to yield the title product as yellow crystals (1.94 g, 61%), m.p. 251–
253◦C. [C15H15N3S2O2] (333.44). Required: C, 54.03%; H, 4.53%; N,

Thieno- and Thiazolothieno-Pyrimidine Derivatives
2189
12.60%. Found: C, 53.71%; H, 4.35%; N, 12.51%.IR (KBr) cm−1:3455
(broad OH and NH), 2930 (CH alkyl) and 1691 (CO).1H-NMR (DMSO-
d6)δ ppm: 1.73 (m, 4H, 2CH2), 2.25 (s, 3H, CH3), 2.70 (t, 2H, CH2),
2.80 (s, 3H, CH3), and 2.85 (t, 2H, CH2) and 10.25 (br s, 1H, NH, D2O
exchangeable). MS (EI+Q1 MS LMR UP LR): 332 (M-1) 100%.
2-(Acetothiosemicarbazone)-3-methylthiazolo [3‘, 2‘-a]-6,
7,8,9-tetrahydrocyclohexeno-thieno [2,3-d]
pyrimidin-(5H)-5-one 10
A mixture of compound 8 (3.36 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 (30 ml) to yield the title product as
yellow crystals (3.36 g, 68%), m.p. 247–249◦C. [C15H15N5S3O] (391.54).
Required: C, 49.08%; H, 4.37%; N, 17.88%. Found: C, 48.70%; H, 4.11%;
N, 17.56%. IR (KBr) cm−: 1 3344 (NH2), 3150 (NH), 2929 (CH alkyl) and
1690 (CO).1H-NMR (DMSO-d6)δ ppm:1.70 (m, 4H, 2CH2), 2.30 (s, 3H,
CH3), 2.70 (t, 2H, CH2), 2.78 (s, 3H, CH3), 2.85 (t, 2H, CH2) , 8.15 (br s,
2H , NH2, D2O exchangeable), and 11.65(br s, 1H, NH, D2O exchange-
able). MS (EI+Q1 MS LMR UP LR): 390.5 (M+); 100%.
2-Cinnamoyl (derivatives)-3-methylthiazolo [3‘, 2‘-a]-6, 7,
8,9-tetrahydrocyclohexeno-thieno [2, 3-d] pyrimidin-
(5H)-5-one 11a,b—General Procedure
A mixture of compound 8 (3.36 g, 0.01 mol), the proper aromatic alde-
hyde (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 cool-
ing and addition of methanol (50 ml). The precipitate so-formed was
collected by filtration and recrystallized from the proper solvent to pro-
duce 11a,b.
2-Cinnamoyl-3-methyl-thiazolo[3‘,2‘-a]-6,7,8,9-
tetrahydrocyclohexenothieno[2,3-d]-
pyrimidin-(5H)-5-one 11a
From compound 8 (3.18 g, 0.01 mole) and benzaldehyde (1.06 g,
0.01 mol).The compound was recrystallized from dioxane (30 ml) to
yield the title compound as yellow crystals (2.40 g, 59%), m.p. 253–
255◦C. [C22H18N2S2O2] (406.52). Required: C, 65.00%; H, 4.46%; N,
6.89%. Found: C, 64.71%; H, 4.33%; N, 6.54%. IR (KBr) cm−: 1 3030 (CH

2190
Kh. M. Abu-Zied
aromatic), 2926 (CH alkyl) and 1710, 1680 (2CO).1H-NMR (CDCl3)δ
ppm: 1.76 (m, 4H, 2CH2), 2.75 (t , 2H , CH2), 2.88 (t , 2H , CH2), 3.15
(s , 3H , CH3), 7.15 (d, 1H, J = 10Hz , ethylenic proton), 7.55–7.86 (m ,
5H, phenyl protons), and 7.90 (d, 1H , J = 10Hz , ethylenic proton). MS
(EI + Q1 MS LMR UP LR): 406.5 (M+) 100%.
2-(p-Methoxycinnamoyl)-3-methylthiazolo [3‘,
2‘-a]-6,7,8,9-tetrahydrocyclohexeno-thieno [2,3-d]
pyrimidin-(5H)-5-one 11b
From compound 8 (3.18 g, 0.01 mol) and 4-methoxy benzaldehyde
(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. [C23H20N2S2O3] (436.55) Required: C, 62.54%; H, 4.29%; N,
6.63. Found: C, 62.31%; H, 3.91%; N, 6.50%. IR (KBr) cm−1:3025 (CH),
2929 (CH alkyl) and 1693, 1680 (2CO).1H-NMR (DMSO-d6)δ ppm: 1.70
(m , 4H , 2CH2), 2.22 (s, 3H , CH3), 2.77(t , 2H CH2), 2.90 (t, 2H, CH2),
3.45 (s , 3H, CH3) 7.05 (d, 1H, J = 13Hz, ethylenic proton), 7.60–7.80
(m, 4H , phenyl protons), and 7.77 (d, 1H, J = 13Hz, ethylenic proton ).
MS (EI + Q1 MS LMR UP LR): 436.5 (M+) 89.60%.
2-Alkylthio-3-alkyl-5,6,7,8-tetrahydrocyclohexenothieno[2,3-
d]pyrimidin-(4H)-4- one 12a,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 5c (0.01 mol), the heating was continued
for 30 min, and 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, and then cooled to room temperature and
poured into cold water (100 ml). The solid so-precipitated was filtered-
off, washed with water, dried, and recrystallized from appropriate sol-
vent to produce 12a,b.
2-Methylthio-3-ethyl-5,6,7,8-tetrahydrocyclohexenothieno-
[2,3-d]pyrimidin-(4H)-4-one 12a
From compound 5a (2.52 g, 0.01 mol) and ethyl iodide (2.10g,
0.012 mol). The compound was recrystallized from ethanol (30 ml) to
yield the title product as a colorless crystals (2.30 g, 82%), m.p. 211–
213◦C. [C13H16N2S2O] (280.41). Required: C, 55.68 %; H , 5.75 % ; N,
9.98 % ;S , 22.86% .Found: C, 55.55%; H, 5.61%; N, 9.70%;S , 22.70 %.
IR (KBr) cm−: 12922 (CH alkyl) and 1675 (CO).1H-NMR (CDCl3)δ ppm:
1.40 (t, 3H, CH3), 1.75 (m, 4H, 2CH2), 2.64 (s, 3H, CH3), 2.80 (t, 2H,

Thieno- and Thiazolothieno-Pyrimidine Derivatives
2191
CH2), 2.86 (t, 2H, CH2), and 4.15 (q, 2H, CH2). MS (EI + Q1 MS LMR
UP LR): 280.4 (M+) 86.20%.
2-Ethylthio-3-methyl-5,6,7,8-tetrahydrocyclohexenothieno-
[2,3-d]pyrimidin-(4H)-4-one 12b
From compound 5c (2.66 g, 0.01 mol) and methyl iodide (1.82 g, 0.012
mol). The compound was recrystallized from ethanol (25 ml) to yield the
title product as a colorless crystals (2.04 g, 78.40%), mp. 193–195◦C.
[C13H16N2S2O] (280.41). Required: C, 55.68%; H, 5.75%; N, 9.89%; S,
22.87 %. Found: C, 55.53%; H, 5.49%; N, 9.64%, S; 22.67%. IR (KBr)
cm−: 1 2930 (CH alkyl) and 1668 (CO).1H-NMR (CDCl3)δ ppm: 1.43 (t,
3H, CH3), 1.75 (m, 4H, 2CH2), 2.66 (s, 3H, CH3), 2.75 (t, 2H, CH2), 2.88
(t, 2H, CH2), and 4.20 (q, 2H, CH2). MS (EI + Q1 MS LMR UP LR): 279
(M+) 93.10%.
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