Synthesis and reactions of polynuclear heterocycles: Azolothienopyrimidines and thienothiazolopyrimidines

Article abstract of DOI:10.1080/10426500600864536

We prepared a thieno[2,3-d]pyrimidine compound fused with a thiazolo ring to produce biologicaly active compounds. In a one-step reaction, 2-arylmethylene derivative (3) was prepared via the reaction of a ternary mixture of 2-thioxo-1,2,3,4-tetrahydrocycl

Full text of DOI:10.1080/10426500600864536

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Synthesis and Reactions of
Polynuclear Heterocycles:
Azolothienopyrimidines and
Thienothiazolopyrimidines
A. B. A. El-Gazzar a , H. A. R. Hussein a & A. S. Aly a
a Photochemistry Department (Heterocyclic Unit),
National Research Center , Dokki, Cairo, Egypt
Published online: 22 Nov 2006.
To cite this article: A. B. A. El-Gazzar , H. A. R. Hussein & A. S. Aly (2006)
Synthesis and Reactions of Polynuclear Heterocycles: Azolothienopyrimidines and
Thienothiazolopyrimidines, Phosphorus, Sulfur, and Silicon and the Related Elements,
181:12, 2771-2784, DOI: 10.1080/10426500600864536
To link to this article: http://dx.doi.org/10.1080/10426500600864536
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Phosphorus, Sulfur, and Silicon, 181:2771–2784, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600864536
Synthesis and Reactions of Polynuclear Heterocycles:
Azolothienopyrimidines and Thienothiazolopyrimidines
A. B. A. El-Gazzar
H. A. R. Hussein
A. S. Aly
Photochemistry Department (Heterocyclic Unit), National Research
Center, Dokki, Cairo, Egypt
We prepared a thieno[2,3-d]pyrimidine compound fused with a thiazolo ring to
produce biologicaly active compounds. In a one-step reaction, 2-arylmethylene
derivative (3) was prepared via the reaction of a ternary mixture of 2-thioxo-
1,2,3,4-tetrahydrocyclohepteno[4,5]thieno[2,3-d]pyrimi-dine-4-one (2), cloroacetic
acid, and a proper aldehyde. The reaction of 2 with 3-chloropent-2,4-dione in
ethanolic potassium hydroxide yielded the S-acetylacetone derivative 4e. The lat-
ter compound reacted with hydrazine hydrate and phenyl hydrazine to give 2-
pyrazolthio derivatives 8a,b, respectively. Compound 4e also underwent cycliza-
tion on boiling with acetic anhydride/pyridine solution to form 2-acetyl-3-methyl
thiazolo[3,2-a]cyclohepteno[4,5]thieno[2,3-d] pyrimidine-5-one (9). To support the
structure 9, it gave a characteristic reaction for the 2-acetyl group. The 2-methylthio
derivatives 4a underwent further alkylation at N to give 6a,b. The purpose of the
3
synthesis of thienopyrimidine derivatives is due to high biological activities. The
4-oxo-thienopyrimidine derivatives acted as inhibitors of adenosine kinase, platelet
aggregation, antilukemia, and anticancer activities.
Keywords Mass spectra; NMR spectra; polynuclear; pyrimidines
DISCUSSION
Our interest in thieno[2,3-d]pyrimidine synthesis emerges from numer-
ous reports on their diverse biological activities. We report here the syn-
theses of new polynuclear heterocyclic thienopyrimidine derivatives,
starting with 2-thioxo-1,2,3,4-tetrahydrocyclopenteno[4,5]thieno[2,3-
d]pyrimidine-4-one (2), which is a versatile intermediate for the
preparation of polyheretocycles due to the presence of reactive func-
tional groups.
Received November 14, 2005; accepted May 3, 2006.
Address correspondence to A. S. Aly, National Research Center, Photochemistry
Department (Heterocyclic Unit), Dokki, Cairo, Egypt. E-mail: a s aly@yahoo.com
2771

2772
A. B. A. El-Gazzar et al.
SCHEME 1
Thus heating under reflux ethyl 2-amino-cyclohepteno[b]thiophene-
3-carboxylate (1), prepared according to Karl Gewald method,1−3 with
potassium thiocyanate in dry dioxane in the presence of hydrochloric
acid, followed by cyclization with acetic acid, yielded compound 2 in a
good yield (Scheme 1).
The IR spectrum of 2 displayed absorption bands at 3414 cm−1 (NH)
and 1660 cm−1 (CO).
Its 1H-NMR spectrum (DMSO-d6) showed signals at δ 1.65 ppm (m,
4H, 2CH2), δ 1.85 (m, 2H, CH2), δ 2.90 (m, 2H, CH2), δ 3.20 (m, 2H,
CH2), δ 12.30 (br, s, 1H, NH, D2O exchangeable), and δ 13.30 (br, s, 1H,
NH, D2O exchangeable). The mass spectrum of 2 showed the molocular
ion peak at m/z 252.
On heating under reflux a mixture of compound 2, chloroacetic acid,
aromatic aldehyde in acetic acid, and acetic anhydride in the presense
of anhydrous soduim acetate, heterocycles 3a–c were obtained in a good
yield (Scheme 2).
The assignment of structure 3 to the reaction products was based on
1. correct values in elemental analyses and compatible IR spectral data
(Experimental);
SCHEME 2

Synthesis and Reactions of Polynuclear Heterocycles
2773
SCHEME 3
2. 1H-NMR and mass spectra (Experimental); and
3. it is reported in the literature that the N-3 nitrogen atom4,5 and not
the N-1 nitrogen atom is involved in the cyclization.
The alkylation of compound 2 in ethanolic potassium hydroxide
solution or chloro-compounds yielded the 2-alkythio derivatives 4a–f
(Scheme 3). With hydrazine hydrate, compounds 4a,b gave the 2-
hydrazino derivative 5. This is conclusive for structures 4a,b.
The 2-alkylthio derivatives 4a,b underwent further alkylation on
treatment with alkyl iodide in aqueous ethanolic potassium ethoxide,
the N-3 alkylated products 6a,b (Scheme 3). The structural assignment
of 6 is based on an independent preparation of 6b by the methylation
of compound 7 with methyl iodide.4
On the other hand, compound 4e reacted as 1,3-diketone with hy-
drazine hydrate and phenyl hydrazine to afford the cyclized products
8a,b (Scheme 4).
IR spectra of these compounds displayed absorption bands around
1
1660 cm−1 (CO). The H-NMR spectrum (DMSO-d6) of 8a showed sig-
nals at δ 1.65 ppm (m, 4H, 2CH2), δ 1.85 (m, 2H, CH2), δ 2.20 (s, 6H,
2CH3), δ 2.90 (m, 2H, CH2), δ 3.20 (m, 2H, CH2), and δ 12.60 (br, s, 1H,
NH, D2O exchangeable).
Heating 4e in a mixture of acetic anhydride/pyridine led to the for-
mation of the cyclic product 9. The IR spectrum of 9 displayed two

2774
A. B. A. El-Gazzar et al.
SCHEME 4
1
carbonyl absorption bands at 1694 and 1671 cm−1. Its H-NMR spec-
trum (DMSO-d6) showed signals at δ 1.65 ppm (m, 4H, 2CH2), δ 1.85
(m, 2H, CH2), δ 2.60 (s, 3H, CH3), δ 2.90 (m, 2H, CH2), δ 3.10 (s, 3H,
CH3), and δ 3.20 (m, 2H, CH2).
Ketone compound 9 formed an oxime 10. Moreover, the conden-
sation of 9 with aromatic aldehydes furnishes the derivatives 11a–c
(Scheme 4). The IR of 11 displayed two carbonyl absorption bands
1
around 1700 and 1650 cm−1 (2CO). The H-NMR spectrum (CDCl3)
of 11b showed signals at δ 1.70 ppm (m, 4H, 2CH2), δ 1.90 (m, 2H,
CH2), δ 2.80 (m, 2H, CH2), δ 3.20 (s, 3H, CH3), δ 3.30 (m, 2H, CH2),
δ 7.10 (d, 1H, ethylenic proton), δ 7.45 (d, 2H, aromatic protons), δ 7.65
(d, 2H, aromatic protons), and δ 7.85 (d, 1H, ethylenic proton).
Also, when compound 4f was heated with polyphosphoric
acid, it afforded 3-phenylthiazolo[3,2-a]cyclohepteno[4,5]thieno[2,3-
d]pyrimidine-5(5H)-one (12) (Scheme 5). The IR spectrum of 12 dis-
1
played an absorption band at 1695 cm−1(CO). Its H-NMR spectrum

Synthesis and Reactions of Polynuclear Heterocycles
2775
SCHEME 5
(DMSO-d6) showed signals at δ 1.65 ppm (m, 4H, 2CH2), δ 1.85 (m, 2H,
CH2), δ 2.90 (m, 2H, CH2), δ 3.30 (m, 2H, CH2), δ 7.20 (s, 1H, thiazolo
proton), and δ 7.55 (m, 5H, aromatic protons). The mass spectrum of 12
showed the molecular ion peak at m/z 352.
EXPERIMENTAL
All melting points are uncorrected and were taken in open capillaries
on a Gallen Kamp Apparatus. Microanalyses were carried out at the
microanalytical units, National Research Center and Faculty of Science,
Cairo University (Table I). IR spectra were carried out at a FT/IR-300 E
1
Jasco using KBr discs. H-NMR spectra were measured in DMSO or
CDCl3, using a 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.
2-Thioxo-1,2,3,4-tetrahydrocyclohepteno[4,5]thieno[2,3-
d]pyrimidin-4-one (2)
A mixture of 1 (2.39 g, 0.01 mole), potassium thiocyanate (0.97 g, 0.01
mole), and concentrated hydrochloric acid (30 mL) was refluxed in diox-
ane (30 mL) for 5 h (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. The precipitate that
formed was cyclized by heating in glacial acitic acid and anhydrous
sodium acetate to afford a colorless precipitate. The formed precipitate
was collected by filtration, washed with water, and recrystallized from
dioxane to produce a colorless powder 2; IR spectrum (KBr) cm−1: 3414
(NH); 2920 (CH aliphatic) and 1660 (CO); 1H-NMR (DMSO-d6) δ ppm:
1.65 (m, 4H, 2CH2), 1.85 (m, 2H, CH2), 2.90 (m, 2H, CH2), 3.20 (m, 2H,
CH2), 12.30 (br s, 1H, NH, D2O exchangeable) and 13.30 (br s, 1H, NH,
D2O exchangeable); MS (m/z): 252.0 (M+) 100%.

2776
A. B. A. El-Gazzar et al.
TABLE I Physical Data for Products 2–12
Elemental analyses
(Calcd./Found)
Compound
No.
Yield
%
M.F.
(M. Wt.)
M.P.◦C
%C
%H
%N
2
308–310◦C
70
80
80
80
65
67
62
65
85
72
73
82
67
82
58
81
67
61
59
58
63
C11H12N2S2O
252.34
C20H16N2S2O2
380.48
C20H15N2S2O2Cl
414.94
C21H18N2S2O3
410.51
C12H14N2S2O
266.38
C13H16N2S2O
280.41
C13H14N2S2O3
310.39
C15H18N2S2O3
338.44
C16H18N2S2O3
350.46
C19H18N2S2O2
370.49
C11H14N4SO
250.32
C13H16N2S2O
280.41
C14H18N2S2O
294.43
C16H18N4S2O
346.47
C22H22N4S2O
422.57
C16H16N2S2O2
332.44
52.35
52.40
63.13
63.40
57.89
57.90
61.44
61.42
54.10
54.60
55.68
56.08
50.30
50.29
53.23
53.00
54.83
54.90
61.59
61.70
52.78
52.90
55.68
55.70
57.11
56.70
55.46
55.33
62.53
62.30
57.80
57.79
55.30
55.80
65.68
65.60
60.71
60.70
63.97
63.90
64.74
64.66
4.79
4.75
4.23
4.90
3.64
3.60
4.41
4.50
5.29
5.00
5.75
5.56
4.54
4.85
5.36
5.40
5.17
5.00
4.89
4.60
5.63
5.70
5.75
4.90
6.16
5.90
5.23
5.28
5.24
5.30
4.85
4.98
4.93
5.10
4.79
4.50
4.20
4.30
4.92
5.04
4.57
4.29
11.10
11.10
7.36
7.36
6.75
6.75
6.82
6.82
10.51
10.50
9.98
10.10
9.02
9.00
8.27
8.27
7.99
7.90
7.56
7.56
22.38
22.35
9.98
9.50
9.51
9.78
16.17
16.10
13.25
13.15
8.42
8.40
12.09
12.00
6.66
6.60
6.15
6.10
6.21
6.28
7.94
8.02
3a
3b
3c
4a
4b
4c
4d
4e
4f
288–290◦C
298–300◦C
300–302◦C
257–259◦C
212–214◦C
243–245◦C
180–182◦C
237–239◦C
224–226◦C
300–302◦C
145–147◦C
150–152◦C
299–301◦C
223–225◦C
189–191◦C
260–62◦C
5
6a
6b
8a
8b
9
10
11a
11b
11c
12
C16H17N3S2O3
347.45
C23H20N2S2O2
420.55
C23H19N2S2O2Cl
454.99
C24H22N2S2O3
450.58
245–147◦C
230–132◦C
215–217◦C
214–216◦C
C19H16N2S2O
352.47

Synthesis and Reactions of Polynuclear Heterocycles
2777
2-Arylmethylene-2H-thiazolo[3,2-a]cyclohepteno[4,5]thieno[
2,3-d]pyrimidine-3(3H), 5(5H)dione 3a–c
General Procedure: Method A
A mixture of compound 2 (2.52 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 dimethylformamide to produce 3a–c.
Method B
Compound 4c (3.10 g, 0.01 mole) was heated under reflux with the
proper aldehyde in acetic acid (30 mL) and acetic anhydride (15 mL),
in the presence of anhydrous sodium acetate (0.02 mole), for 5 h. The
reaction mixture was then cooled and poured into water. The deposited
precipitate was filtered-off and recrystallized from dimethylformamide
to yield the title product.
2-(Phenylmethylene)-2H-thiazolo[3,2-a]cyclohepteno[4,5]-
thieno[2,3-d]pyrimidine-3(3H), 5(5H)-dione (3a)
Compound 3a was obtained from 2 (2.52 g, 0.01 mole) and benzaldehyde
(1.06 g, 0.01 mole). The compound was recrystallized from dimethylfor-
mamide to produce 3a as pale yellow crystals; IR spectrum (KBr) cm−1
:
2921 (CH); 1758 (CO) and 1697 (CO); 1H-NMR (DMSO-d6) δ ppm: 1.65
(m, 4H, 2CH2), 1.85 (m, 2H, CH2), 2.90 (m, 2H, CH2), 3.30 (m, 2H, CH2),
7.50–7.70 (m, 5H, phenyl protons) and 8.00 (s, 1H, CH); MS (m/z): 379.9
(M+) 100%.
2-(4-Chlorophenylmethylene)-2H-thiazolo[3,2-
a]cyclohepteno[4,5]thieno[2,3-d]pyrimidine-3(3H),
5(5H)-dione (3b)
Compound 3b was obtained from 2 (2.52 g, 0.01 mole) and 4-
chlorobenzaldehyde (1.40 g, 0.01 mole). The product was recrystallized
from dimethylformamide to produce 3b as yellow crystals; IR spectrum
1
(KBr) cm−1: 2913 (CH), 1758 (CO) and 1685 (CO); H-NMR (DMSO-
d6) δ ppm: 1.65 (m, 4H, 2CH2), 1.85 (m, 2H, CH2), 2.90 (m, 2H, CH2),
3.20 (m, 2H, CH2), 7.75 (d, 2H, aromatic protons), 7.85 (d, 2H, aromatic
protons) and 8.00 (s, 1H, ethylenic proton); MS (m/z): 414.0 (M+) 100%.

2778
A. B. A. El-Gazzar et al.
2-(4-Methoxyphenylmethylene)-2H-thiazolo[3,2-a]cyclo-
hepteno[4,5]thieno[2,3-d]pyrimidine-3(3H),5(5H)-dione (3c)
Compound 3c was obtained from 2 (2.52 g, 0.01 mole) and 4-
methoxybenzaldehyde (1.36 g, 0.01 mole). The compound was recrystal-
lized from dimethylformamide to produce 3c orange crystals; IR spec-
trum (KBr) cm−1: 2900 (CH), 1749 (CO) and 1675 (CO); MS (m/z): 410
(M+) 100%.
2-(Alkylthio)-3H-cyclohepteno[4,5]thieno[2,3-d]pyrimidin-
4(4H)-one 4a–f
General Method
To a warmed ethanolic potassium hydroxide solution [prepared by
dissolving potassium hydroxide (0.56 g, 0.01 mole) in ethanol (50 mL)]
was added compound 2 (2.52 g, 0.01 mole); it was heated for 30 min,
and the mixture was allowed to cool to r.t. the proper halo compound
(0.01 mole) was added. The mixture was heated under reflux, filtered
off, recrystallized from appropriate solvent to for 5 h, and then cooled
and poured into water. The solid product so-precipitated produced 4a–f.
2-(Methylthio)-3H-cyclohepteno[4,5]thieno[2,3-d]pyrimidine-
4(4H)-one (4a)
Compound 4a was obtained from 2 (2.52 g, 0.01 mole) and methyl iodide
(1.72 g, 0.013 mole). The compound was recrystallized from dioxane to
produce 4a as colorless crystals; IR spectrum (KBr) cm−1: 3448 (NH);
2917 (CH aliphatic) and 1654 (CO); 1H-NMR (DMSO-d6) δ ppm: 1.65 (m,
4H, 2CH2), 1.85 (m, 2H, CH2), 2.50 (s, 3H, CH3), 2.90 (m, 2H, CH2), 3.20
(m, 2H, CH2), and 12.60 (br s, 1H, NH, D2O exchangeable); 13C-NMR
(DMSO-d6) δ ppm: 31.9, 28.8, 27.3, 27.1, 26.8, and 12.8 (five CH2+ one
CH3); 119.4, 134.3, 136.1, 155.9, and 158.5 (thienopyrimidine carbon
atoms); MS (m/z): 266.0 (M+) 100%.
2-(Ethylthio)-3H-cyclohepteno[4,5]thieno[2,3-d]pyrimidin-
4(4H)-one (4b)
Compound 4b was obtained from 2 (2.52 g, 0.01 mole) and ethyl iodide
(1.86 g, 0.012 mole). The compound was recrystallized from ethanol to
produce 4b as colorless crystals; IR spectrum (KBr) cm−1: 3567 (NH);
1
2928 (CH) and 1670 (CO); H-NMR (CDCl3) δ ppm: 1.40 (t, 3H, CH3),
1.75 (m, 4H, 2CH2), 1.85 (m, 2H, CH2), 2.90 (m, 2H, CH2), 3.20 (m, 2H,
CH2), 3.40 (m, 2H, CH2) and 10.90 (br s, 1H, NH, D2O exchangeable).
MS (m/z): 280.1 (M+) 100%.

Synthesis and Reactions of Polynuclear Heterocycles
2779
2-(Carboxymethylthio)-3H-cyclohepteno[4,5]thieno[2,3-
d]pyrimidin-4(4H)-one (4c)
Compound 4c was obtained from 2 (2.52 g, 0.01 mole) and chloroactetic
acid (1.14 g, 0.01 mole). The compound was recrystallized from
dimethylformamide to produce 4c as colorless crystals; IR spectrum
1
(KBr) cm−1: 3444 (OH); 1690 (CO) and 1655 (CO); H-NMR (DMSO-
d6) δ ppm: 1.65 (m, 4H, 2CH2), 1.85 (m, 2H, CH2), 2.70 (m, 2H, CH2),
3.20 (m, 2H, CH2), 4.00 (s, 2H, CH2) and 12.60 (br s, 2H, 2(OH), D2O
exchangeable); MS (m/z): 310.0 (M+).
2-(Ethoxycarbonylmethylthio)-3H-
cyclohepteno[4,5]thieno[2,3-d]pyrimidin-4(4H)-one (4d)
Compound 4d was obtained from 2 (2.52 g, 0.01 mole) and ethyl
chloroacetate (1.22 g, 0.01 mole). The compound was recrystallized from
ethanol to produce 4d as colorless crystals; IR spectrum (KBr) cm−1
:
1
3458 (NH); 2981 (CH aliphatic), 1741 (CO) and 1655 (CO); H-NMR
(CDCl3) δ ppm: 1.40 (t, 3H, CH3), 1.65 (m, 4H, 2CH2), 1.85 (m, 2H,
CH2), 2.70 (m, 2H, CH2), 3.20 (m, 2H, CH2), 3.90 (s, 2H, CH2), 4.30 (q,
2H, CH2) and 11.70 (br s, 1H, NH, D2O exchangeable); MS (m/z): 338.1
(M+) 100%.
2-(Diacetylmethylthio)-3H-cyclohepteno[4,5]thieno[2,3-
d]pyrimidin-4(4H)-one (4e)
Compound 4e was obtained from 2 (2.52 g, 0.01 mole) and chloroacety-
lacetone (1.61 g, 0.012 mole). The compound was recrystallized from
dioxane to produce 4e as colorless crystals; IR spectrum (KBr) cm−1
:
3444 (broad NH and OH); 2979 (CH aliphatic), 1683 (CO) and 1653
1
(CO); H-NMR (DMSO-d6) δ ppm: 1.55 (m, 4H, 2CH2), 1.85 (m, 2H,
CH2), 2.30 (s, 6H, 2CH3), 2.75 (m, 2H, CH2), 3.10 (m, 2H, CH2) and
12.80 (br s, 1H, NH, D2O exchangeable); MS (m/z): 350.0 (M+) 32.6%
and 332 (M-18) 100%.
2-(Benzoylmethylthio)-3H-cyclohepteno[4,5]thieno[2,3-
d]pyrimidine-4(4H)-one(4f)
Compound 4f was obtained from 2 (2.52 g, 0.01 mole) and ω–
bromoacetophenone (2.38 g, 0.012 mole). The compound was crystal-
lized from dioxane to produce 4f as colorless crystals; IR spectrum (KBr)
cm−1: 3447 (broad OH); 3062 (CH aromatic), 2917 (CH aliphatic), 1683
(CO); 1H-NMR (DMSO-d6) δ ppm: 1.65 (m, 4H, 2CH2), 1.85 (m, 2H,
CH2), 2.70 (m, 2H, CH2), 3.20 (m, 2H, CH2), 4.80 (s, 2H, CH2), 7.40–8.15
(m, 5H, aromatic protons) and 12.70 (br s, 1H, NH, D2O exchangeable);
MS (m/z): 370 (M+) 100%.

2780
A. B. A. El-Gazzar et al.
2-Hydrazino-3H-cyclohepteno[4,5]thieno[2,3-d]pyrimidine-
4(4H)-one (5)
A mixture of 4a (2.66 g, 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, filtered off, and recrystal-
lized from dimethylformamide to produce 5 as colorless crystals; IR
spectrum (KBr) cm−1: 3341; 3178 [(NH2), (NH)]; 2914 (CH aliphatic)
1
and 1657 (CO); H-NMR (DMSO-d6) δ ppm: 1.70 (m, 4H, 2CH2), 1.85
(m, 2H, CH2), 2.70 (m, 2H, CH2), 3.20 (m, 2H, CH2), 4.60 (br, 1H,
NH, D2O exchangeable) and 8.20 (br s, 1H, NH, D2O exchangeable);
13C-NMR(DMSO-d6) δ ppm: 27.0, 27.3, 27.6, 28.8, and 32.0 (five CH2);
114.7, 128.5, 135.6, 154.3 and 158.4 (thienopyrimidine carbon atoms)
and 165.1 (CO); MS (m/z): 250.1 (M+) 100%.
2-Alkylthio-3-alkyl-3H-cyclohepteno[4,5]thieno[2,3-
d]pyrimidine-4(4H)-one 6a,b
General Procedure
To a warmed ethanolic potassium hydroxide solution (prepared by
dissolving (0.56 g, 0.01 mole in 50 mL of ethanol) was added compound
4a (0.01 mole). Heating was continued for 30 min, and the mixture was
allowed to cool; the proper alkyl iodide (0.012 mole) was added. The
mixture was heated under reflux for 4 h, cooled at r.t., poured into cold
water. The solid so-precipitated was filtered off, washed with water, and
recrystallized from the appropriate solvent to produce 6a,b.
2-Methylthio-3-methyl-3H-cyclohepteno[4,5]thieno[2,3-
d]pyrimidine-4(4H)-one(6a)
Compound 6a was obtained from 4a (2.66 g, 0.01 mole) and methyl io-
dide (1.72 g, 0.012 mole). The compound was recrystallized from ethanol
to produce compound 6a as colorless crystals; IR spectrum (KBr) cm−1
2916 (CH aliphatic) and 1667 (CO); H-NMR (CDCl3) δ ppm: 1.70 (m,
4H, 2CH2), 1.85 (m, 2H, CH2), 2.60 (s, 3H, CH3), 2.90 (m, 2H, CH2),
3.30 (m, 2H, CH2) and 3.65 (s, 3H, CH3); MS (m/z): 280 (M+) 100%.
:
1
2-Methylthio-3-ethyl-3H-cyclohepteno[4,5]thieno[2,3-
d]pyrimidine-4(4H)-one(6b)
Compound 6b was obtained from 4a (2.66 g, 0.01 mole) and ethyl iodide
(1.86 g, 0.012 mole). The compound was recrystallized from ethanol to
produce compound 6b as colorless crystals; IR spectrum (KBr) cm−1
:

Synthesis and Reactions of Polynuclear Heterocycles
2781
1
2918 (CH aliphatic) and 1664 (CO); H-NMR (CDCl3) δ ppm: 1.30 (t,
3H, CH3), 1.70 (m, 4H, 2CH2), 1.85 (m, 2H, CH2), 2.50 (s, 3H, CH3),
2.80 (m, 2H, CH2), 3.30 (m, 2H, CH2) and 4.20 (q, 2H, CH2); MS (m/z):
294 (M+) 100%.
2-(3,5-Dimethyl–1-(un)substitutedpyrazol-4-ylthio)-3H-
cyclohepteno[4,5]thieno[2,3-d]pyrimidin-4(4H)-one 8a,b
General Procedure
A mixture of compound 4e (3.50 g, 0.01 mole) and hydrazine hy-
drate (99–100%) or phenyl hydrazine hyrochloride (0.01 mole) in diox-
ane and ethanol was stirred under reflux for 10 h. The reaction mixture
was allowed to cool to r.t. and poured into water. The solid product so-
precipitated was filtered off and recrystallized from dioxane to produce
8a,b.
2-(3,5-Dimethyl–1H-pyrazol-4-ylthio)-3H-
cyclohepteno[4,5]thieno[2,3-d]pyrimidine-4(4H)-one (8a)
Compound 8a was obtained from a mixture of 4e (3.50 g, 0.01 mole) and
hydrazine hydrate (10 mL). The compound was recrystallized from diox-
ane to produce compound 8a as colorless crystals; IR spectrum (KBr)
1
cm−1: 3447 (NH), 3230 (NH), 2920 (CH aliphatic) and 1662 (CO); H-
NMR (DMSO-d6) δ ppm: 1.65 (m, 4H, 2CH2), 1.85 (m, 2H, CH2), 2.20 (s,
6H, 2CH3), 2.80 (m, 2H, CH2), 3.20 (m, 2H, CH2) and 12.60 (br s, 1H,
NH, D2O exchangeable); MS (m/z): 346 (M+) 100%.
2-(3,5-Dimethyl–1-phenylpyrazol-4-ylthio)-3H-
cyclohepteno[4,5]thieno[2,3-d]pyrimidin-4(4H)-one (8b)
Compound 8b was obtained from a mixture of 4e (3.50 g, 0.01 mole)
and phenyl hydrazine hydrochloride (1.45 g, 0.01 mole). The compound
was recrystallized from dioxane to produce compound 8b as light yellow
crystals; IR spectrum (KBr) cm−1: 3286 (NH), 2913 (CH aliphatic) and
1
1683 (CO); H-NMR (DMSO-d6) δ ppm: 1.65 (m, 4H, 2CH2), 1.85 (m,
2H, CH2), 2.30 (s, 3H, CH3), 2.80 (m, 2H, CH2), 2.95 (s, 3H, CH3), 3.30
(m, 2H, CH2), 6.85–7.30 (m, 5H, aromatic protons) and 9.70 (br s, 1H,
NH, D2O exchangeable); MS (m/z): 422 (M+) 100%.

2782
A. B. A. El-Gazzar et al.
2-Acetyl-3-methylthiazolo[3,2-a]-cyclohepteno[4,5]thieno[2,3-
d]pyrimidin-5(5H)-one (9)
A solution of compound 4e (3.50 g, 0.01 mole) in (10 mL) acetic an-
hydride and (20 mL) of pyridine was heated under reflux for 5 h. The
reaction mixture was cooled, and the deposited precipitate was filtered-
off and recrystallized from dioxane to produce 9 as yellow crystals; IR
spectrum (KBr) cm−1: 2930 (CH aliphatic), 1694 (CO) and 1671 (CO);
1H-NMR (DMSO-d6) δ ppm: 1.65 (m, 4H, 2CH2), 1.85 (m, 2H, CH2), 2.60
(s, 3H, CH3), 2.90 (m, 2H, CH2), 3.10 (s, 3H, CH3) and 3.20 (m, 2H, CH2);
MS (m/z): 332 (M+) 100%.
2-(Acetoxime)-3-methylthiazolo[3,2-a]-
cyclohepteno[4,5]thieno[2,3-d]pyrimidin-5(5H)-one (10)
A mixture of 9 (3.32 g, 0.01 mole), hydroxylamine hydrochloride (0.70
g, 0.01 mole), and a catalytic amount of piperidine was refluxed in diox-
ane (30 mL) for 6 h. The reaction mixture was allowed to cool to r.t. and
was poured into water. The solid product so-precipitated was filtered
off and recrystallized from dioxane to produce 10 as yellow crystals; IR
spectrum (KBr) cm−1: 3250 (OH), 2917 (CH aliphatic) and 1685 (CO);
1H-NMR (DMSO-d6) δ ppm: 1.70 (m, 4H, 2CH2), 1.85 (m, 2H, CH2),
2.30 (s, 3H, CH3), 2.80 (s, 3H, CH3), 2.90 (m, 2H, CH2), 3.20 (m, 2H,
CH2) and 11.80 (s, 1H, OH, D2O exchangeable); 13C-NMR (DMSO-d6) δ
ppm: 14.4 and 17.1 (two CH3); 26.8, 27.1, 27.3, 29.0 and 32.0 (five CH2);
117.5, 118.8, 133.3, 134.3, 136.3, 148.2 and 157.0 (thiazolothienopyrim-
idine carbon atoms); 157.4 (C NOH); 160.2 (CO); MS (m/z): 347.0 (M+)
100%.
2-Cinnamoyl(derivatives)-3-methylthiazolo[3,2-
a]cyclohepteno[4,5]thieno[2,3-d]pyrimidin-5(5H)-one 11a–c
General Procedure
A mixture of compound 9 (3.32 g, 0.01 mole), the proper aromatic
aldehyde (0.01 mole), and a catalytic amount of piperidine was fused at
170–180◦C for 3 h. The product was solidified by cooling and an addition
of methanol. The precipitate so-formed was collected by filtration and
recrystallized from dioxane to produce 11a–c.
2-Cinnamoyl-3-methyl-thiazolo[3,2-
a]cyclohepteno[4,5]thieno[2,3-d]pyrimidin-5(5H)-one (11a)
Compound 11a was obtained from 9 (3.32 g, 0.01 mole) and benzalde-
hyde (1.06 g, 0.01 mole). The compound was recrystallized from dioxane

Synthesis and Reactions of Polynuclear Heterocycles
2783
to produce 11a as pale yellow crystals; IR spectrum (KBr) cm−1: 2923
1
(CH); 1698 (CO) and 1655 (CO); H-NMR (CDCl3) δ ppm: 1.65 (m, 4H,
2CH2), 1.85 (m, 2H, CH2), 2.90 (m, 2H, CH2), 3.20 (s, 3H, CH3), 3.30 (m,
2H, CH2), 7.15 (d, 1H, CH), 7.40–7.70 (m, 5H, aromatic protons) and
7.8 (d, 1H, CH); MS (m/z): 420.1 (M+) 100%.
2-(4-Chlorocinnamoyl)-3-methylthiazolo[3,2-
a]cyclohepteno[4,5]thieno[2,3-d]pyrimidin-5(5H)-one (11b)
Compound 11b was obtained from 9 (3.32 g, 0.01 mole) and 4-
chlorobenzaldehyde (1.41 g, 0.01 mole). The compound was recrystal-
lized from dioxane to produce 11b as yellow crystals; IR spectrum (KBr)
1
cm−1: 2916 (CH); 1701 (CO) and 1655 (CO); H-NMR (CDCl3) δ ppm:
1.70 (m, 4H, 2CH2), 1.90 (m, 2H, CH2), 2.80 (m, 2H, CH2), 3.20 (s, 3H,
CH3), 3.30 (m, 2H, CH2), 7.10 (d, 1H, CH), 7.45 (d, 2H, aromatic pro-
tons), 7.65 (d, 2H, aromatic protons) and 7.85 (d, 1H, CH); MS (m/z):
454.01 (M+) 100%.
2-(4-Methoxycinnamoyl)-3methyl-thiazolo[3,2-
a]cyclohepteno[4,5]thieno[2,3-d]pyrimidin-5(5H)-one (11c)
Compound 11c was obtained from 9 (3.32 g, 0.01 mole) and 4-
methoxybenzaldehyde (1.36 g, 0.01 mole). The compound was recrys-
tallized from dioxane to produce 11c as yellow crystals; IR spectrum
1
(KBr) cm−1: 2919 (CH); 1698 (CO) and 1654 (CO); H-NMR (CDCl3) δ
ppm: 1.70 (m, 4H, 2CH2), 1.85 (m, 2H, CH2), 2.90 (m, 2H, CH2), 3.30 (s,
3H, CH3), 3.60 (m, 2H, CH2), 3.90 (s, 3H, CH3), 7.00 (d, 1H, CH), 7.00
(d, 2H, aromatic protons), 7.60 (d, 2H, aromatic protons) and 7.80 (d,
1H, CH).
3-Phenylthiazolo[3,2-a]-cyclohepteno[4,5]thieno[2,3-
d]pyrimidin-5 (5H)-one (12)
A mixture of compound 4f (3.70 g, 0.01 mole) and polyphosphoric acid
was heated at 170–180◦C for 2 h. The reaction mixture was allowed to
cool to r.t. and was poured into water. The solid product so-precipitated
was filtered off and recrystallized from dioxane to produce 12 as color-
less crystals; IR spectrum (KBr) cm−1: 3079 (CH aromatic) and 1695
(CO); 1H-NMR (DMSO-d6) δ ppm: 1.65 (m, 4H, 2CH2), 1.85 (m, 2H,
CH2), 2.90 (m, 2H, CH2), 3.30 (m, 2H, CH2), 7.20 (s, 1H, CH) and 7.55
(m, 5H, aromatic protons); MS (m/z): 352.0 (M+) 100%.

2784
A. B. A. El-Gazzar et al.
CONCLUSION
This work is concerned with the synthesis and reactions of thieno[2,3-
d]pyrimidone with functional and bifunctional groups to give pyra-
zolothieno and thiazolothieno derivatives. The work involves carrying
out transformations, which in one or two steps add a new heterocyclic
ring to the molecule.
REFERENCES
[1] K. Gewald, E. Schinke, and H. Bottcher, Ber., 99, 94 (1966).
[2] V. P. Arya, Indian. J. Chem, 10, 1141 (1972).
[3] H. Schaefer, K. Gewald, and M. Seifert, J. Prakt. Chem., 318, 39 (1976).
[4] 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).
[5] S. M. Hussain, A. M. El-Reedy, A. M. H. Rezk, and Kh. A. Sife-Eldien, J. Heterocyclic.
Chem., 24, 1605 (1987).