An efficient synthetic route towards novel 3n-substituted thieno[2,3-d]pyrimidin-4(3H)-ones

Article abstract of DOI:10.3987/COM-15-13236

During the last few years, condensed thienopyrimidine derivatives have received considerable attention. Herewith it has been reported the synthesis of some novel 3N-substituted thieno[2,3-d]pyrimidin-4(3H)-ones appended to different bio-potent moieties ho

Full text of DOI:10.3987/COM-15-13236

HETEROCYCLES, Vol. 91, No. 7, 2015, pp. -. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 27th April, 2015, Accepted, 26th May, 2015, Published online, 8th June, 2015
DOI: 10.3987/COM-15-13236
AN
EFFICIENT
SYNTHETIC
ROUTE
TOWARDS
NOVEL
3
N-SUBSTITUED THIENO[2,3-d]PYRIMIDIN-4(3H)-ONES
Monaem Balti,* Maha Hachicha, and Mohamed Lotfi El Efrit
Laboratory of Organic Chemistry, College of Sciences at Tunis, El Manar
University, Campus 1060 Tunis, Tunisia
E-Mail: baltimoneem@gmail.com; Tel.: +216-21-376-639; Fax: +216-71-871-666
Abstract – During the last few years, condensed thienopyrimidine derivatives
have received considerable attention. Herewith it has been reported the synthesis
of some novel 3N-substituted thieno[2,3-d]pyrimidin-4(3H)-ones appended to
different bio-potent moieties hopping to obtain new derivatives with dual
biological activities.
Heterocycles containing the thienopyrimidine moiety (Figure 1) are of interest because of their interesting
1
-6
pharmacological and biological activities. ꢀThus, over the last two decades many thienopyrimidines
have been found to exhibit a variety of pronounced activities, for example, as antiinflammatory,3,7
antimicrobial,3,8 antiviral and analgesic7,10 agents. Some thienopyrimidine derivatives showed good
antitumor activity,11 while compounds with the general structure designated by C (Figure 1) showed
9
4
potent and specific cytotoxicity against several leukemia cell lines. Motivated by the aforementioned
biological and pharmacological importance of the title compounds, and as continuation with our previous
work on the synthesis of novel heterocyclic systems,12,13 we report herein the synthesis of some new
heterocycles incorporating a thienopyrimidine moiety.
Figure 1. Some biologically active thienopyrimidines

The routes to thieno[2,3-d]pyrimidin-4(3H)-ones mainly involve cyclocondensation of 2-amino-
thiophenes with various electrophilic reagents such as α-substituted acetonitriles,14 formic acid,15
formamide,15 urea ꢀand guanidine. In this paper we wish to report the cyclocondensation of
16
17
2-aminothiophene-3-carboxylates with orthoester in combination with ethanolamine. The synthetic
pathway was planned in such a way to synthesize the thieno[2,3-d]pyrimidin-4(3H)-one ring, in addition
the 3-substituent was selected to incorporate well documented pharmacophoric moieties of interest such
triazole, imidazole and indole. The target compounds were prepared as outlined in Scheme 1.
Scheme 1. Synthetic route for the title compounds 5a-l
The starting materials 2-aminothiophene-3-carboxylate 1a,b derivatives were prepared following the
1
8
method of Gewald via the reaction of cyclohexanone and sulfur with either ethyl cyanoacetate in the
presence of diethylamine.
Initially condensation of 1a,b with orthoester in the presence of acetic acid under reflux gave product
2
a,b which was further refluxed with ethanolamine to gave 3a,b through ring cyclization.
Compounds 3a,b upon reaction with methanesulphonyl chloride in the presence of pyridine gave the
mesylate 4a,b. Finally the title compounds 5a-l were obtained by reacting mesylate 4a,b with various
secondary amines and hydroxyl substituted heterocycles (Scheme 1) under mild basic condition. All the

1
13
newly synthesized compounds were characterized by IR, H and C-NMR and mass spectra. In case of
-1
IR studies, all the compounds have shown a sharp intense band at 1664-1690 cm which corresponds to
carbonyl group of thieno[2,3-d]pyrimidin-4(3H)-one ring. A medium intense band appeared around
1
543-1607 cm-1 was attributed to C=N stretching. In case of 1H-NMR, the C
thieno[2,3-d]pyrimidin-4(3H)-one ring appeared at 2.08-2.75 ppm. The signals appeared at 6.21-8.20 ppm
were attributed to aromatic protons. For 13C-NMR, the
methyl carbon of
thieno[2,3-d]pyrimidin-4(3H)-one ring resonated in the range 21.28-23.66 ppm. The ethyl carbons
showed signals at 30.63-66.16 ppm. A signal resonated at 154.46-159.51 ppm was attributed to C carbon
2
methyl of
C
2
2
of thieno[2,3-d]pyrimidin-4(3H)-one ring. The carbonyl carbon of thieno[2,3-d]pyrimidine ring was
resonated in the range 159.42-162.17 ppm. The other rings attached to alkyl chain have shown signals at
their respective positions.
In summary, the results of the study described above have led to the development of a simple approach
for the synthesis of a novel class of thieno[2,3-d]pyrimidin-4(3H)-one derivatives. Further studies on the
bioactivity of the synthesized compounds are currently under way in our laboratory.
EXPERIMENTAL
Melting points were determined on a Büchi B-545 melting point apparatus and are uncorrected. All
reactions were monitored by thin layer chromatography (TLC). IR spectra were recorded in the range
-1
1
13
4
000-600 cm using KBr disks on a Perkin Elmer 1600 series FTIR spectrometer. H and C-NMR
spectra were recorded with CDCl as the solvent, on a Bruker-300 spectrometer. The chemical shifts are
3
reported in ppm relative to TMS (internal reference). Mass spectra were determined on an Agilent 5975B
spectrometer, under electronicimpact (EI) conditions. Purification of products was performed by column
chromatography using silica gel 60 (Fluka).
General synthetic procedure for thienoiminoethers (2a,b).
A mixture of compound 1a or 1b (20 mmol), triethylorthoacetate (28 mmol) and catalytic amount of
acetic acid was heated under reflux for 3 h. After the completion of the reaction, monitored by TLC,
reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The
residue was chromatographed on a silica gel column, eluting with EtOAc/cyclohexane (1:8) to provide
products 2a,b.
Ethyl (E)-2-((1-ethoxyethylidene)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (2a): Yield:
-1
1
8
9%, mp 68 °C. IR (KBr, cm ): 1656 (C=N), 1692 (C=O). H-NMR (CDCl ): 1.25 (t, J = 7.2 Hz, 3H),
3

1
2
2
1
.31 (t, J = 7.2 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.89 (s, 3H), 1.75 (m, 4H),
.73 (m, 2H), 2.57 (m, 2H). 13C-NMR (CDCl
): 14.55 (CH CH O), 17.02 (CH CH O), 19.57 (CH ),
2.81, 23.34, 26.59, 26.98 (4CH cyclohexane), 59.39 (CH CH O), 62.52 (CH CH O), 115.84, 126.69,
34.40, 157.65 (Cthiophene), 163.83 (C=O), 164.25 (C=N).
3
3
2
3
2
3
2
3
2
3
2
Ethyl
2b): Yield: 86%, mp 77 °C. IR (KBr, cm ): 1576 (C=N), 1659 (C=O). H-NMR (CDCl
Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 4.19 (q, J = 7.2 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.93 (s, 3H),
(E)-2-((1-ethoxyethylidene)amino)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
-1
1
(
3
): 1.29 (t, J = 7.2
1
3
2
.70-2.91 (m, 4H), 3.01 (m, 1H), 2.09 (m, 2H), 7.21-7.33 (m, 5H, CHarom). C-NMR(CDCl
CH CH O), 17.09 (CH CH O), 20.23 (CH ), 27.03, 30.11, 32.75, 40.78 (CH and 3CH cyclohexane),
9.73 (CH CH O), 62.62 (CH CH O), 115.66, 126.15, 126.41, 126.98, 128.57, 134.20, 146.11, 158.19
3
): 14.35
(
3
2
3
2
3
2
5
3
2
3
2
(Carom and Cthiophene), 163.81(C=O), 164.43 (C=N).
General procedure for the preparation of thieno[2,3-d]pyrimidin-4(3H)-ones (3a,b).
An equimolar mixture of the compounds, ethanolamineand catalytic amount of acetic acid in EtOH (15
mL) was heated under reflux for 8 h, then left to cool and the solvent was removed under reduced
pressure. Purification of the residue was carried out by flash silica gel chromatography using
EtOAc/cyclohexane (3:1) as eluent to afford products 3a,b.
3
8
2
-(2-Hydroxyethyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (3a): Yield:
-1
1
4%, mp 145 °C. IR (KBr, cm ): 3468 (OH), 1607 (C=N), 1690 (C=O). H-NMR (CDCl
.66 (s, 3H), 3.97 (t, J = 5.2 Hz, 2H), 4.23 (t, J = 5.2 Hz, 2H), 2.73 (m, 2H), 2.91 (m, 2H). C-NMR
): 22.29, 22.98, 23.41, 25.21, 25.54 (4CH cyclohexane, CH ), 46.95 (CH CH OH), 61.14
CH OH), 120.66, 131.33, 133.21, 146.85 (Cthiophene), 154.46 (C=N), 159.42 (C=O).
3
): 1.82 (m, 4H),
1
3
(
CDCl
CH
3
2
3
2
2
(
2
2
3
-(2-Hydroxyethyl)-2-methyl-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one
-1
1
(
3b): Yield: 82%, mp 169°C. IR (KBr, cm ): 3409 (OH), 1596 (C=N), 1667 (C=O). H-NMR (CDCl
3
):
3
2
.98 (t, J = 5.2 Hz, 2H); 4.26 (t, J = 5.2 Hz, 2H); 2.67 (s, 3H), 2.83-3.00 (m, 4H), 3.08 (m, 1H) 1.96 (m,
1
3
H), 7.21-7.43 (m, 5H, CHarom). C-NMR (CDCl
), 46.95 (CH CH OH), 61.12 (CH
32.76, 145.51 (Carom and Cthiophene), 154.72 (C=N), 159.47 (C=O).
3
): 23.39, 25.89, 29.65, 32.98, 40.61 (CH and 3CH
2
cyclohexane, CH
3
2
2
2
CH
2
OH), 120.53, 126.61, 126.95, 128.68, 131.07,
1
General procedure for the tosylation of compounds (3a,b).
A mixture of compounds (10 mmol), pyridine (20 mmol), and CHCl
3
(20 mL) was placed in a 3-neck

round flask and cooled to 0 °C in an ice bath. Methanesulfonylchloride (15 mmol) was added to the
mixture. The reaction was finished within 2 h. After adding water (10 mL), the resulting mixture was
extracted with Et
2
O (70 mL). The ethereal layer was washed with 2 M aqueous HCl, aqueous NaHCO ,
3
and brine. The solvent was removed by evaporation at reduced pressure, and the residue was
chromatographed on a silica gel column, eluting with EtOAc/cyclohexane (2:5) to give the mesylate 4a,b.
2-(2-Methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethylmethanesulfonate
-
1
(
4a): Yield: 80%, mp 116 °C. IR (KBr, cm ): 1664 (C=O), 1567 (C=N), 1377 and 1155 (O=S=O).
1H-NMR (CDCl
): 1.84 (m, 4H), 2.67 (s, 3H), 3.86 (t, J = 6.4 Hz, 2H), 4.36 (t, J = 6.4 Hz, 2H), 2.74 (m,
H), 2.97 (m, 2H), 3.66 (s, 3H). C-NMR (CDCl
CH ), 40.93 (CH -S), 46.01 (CH CH O SO CH
53.70 (Cthiophene), 158.42 (C=N), 161.74 (C=O).
3
1
3
2
3
): 22.30, 22.98, 23.59, 25.20, 25.55 (4CH
2
cyclohexane,
3
3
2
2
2
3
), 52.61(CH CH OSO CH ), 120.61, 131.37, 133.21,
2
2
2
3
1
2-(2-Methyl-4-oxo-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethylmethane-
-1
sulfonate (4b): Yield: 78%, mp 146 °C. IR (KBr, cm ): 1666 (C=O), 1543 (C=N), 1378 and 1157
1
(
O=S=O). H-NMR (CDCl
3
): 3.88 (t, J = 6.4 Hz, 2H), 4.38 (t, J = 6.4 Hz, 2H), 2.68 (s, 3H), 3.69 (s, 3H),
1
3
2
2
5
.91-3.02 (m, 4H), 3.06 (m, 1H), 1.98 (m, 2H), 7.21-7.34 (m, 5H, CHarom). C-NMR (CDCl
5.91, 29.67, 33.00, 40.63 (CH and 3CH cyclohexane, CH ), 40.97 (CH -S), 46.12 (CH CH OSO
4.82 (CH CH OSO CH ), 120.51, 126.60, 126.96, 128.67, 131.15, 132.77, 145.57, 154.02 (Carom and
thiophene), 158.53 (C=N), 162.08 (C=O).
3
): 23.66,
2
3
3
2
2
2
CH ),
3
2
2
2
3
C
General procedure for the preparation of title compounds (5a-l)
A mixture of compound 4 (10 mmol), appropriate secondary amine (10 mmol) or hydroxyl substituted
compound (10 mmol) and anhydrous K
2
CO (20 mmol) in dry DMF (20 mL) was stirred at 100 °C. The
3
completion of the reaction was checked by TLC using EtOAc and cyclohexane (20%) as eluent. The
reaction mixture was then poured into ice cold water and neutralized with dil. HCl (few drops). The
precipitate thus formed was filtered and dried. All the newly prepared compounds were purified by
column chromatography using EtOAc and cyclohexane (10%) as eluent.
3
-(2-(1H-1,2,4-Triazol-1-yl)ethyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-
-1
1
one (5a): Yield: 91%, mp 147 °C. IR (KBr, cm ): 1668 (C=O), 1543 (C=N). H-NMR (CDCl
3
): 1.85 (m,
4
1
H); 2.26 (s, 3H); 4.44 (t, J = 6.4 Hz, 2H), 4.60 (t, J = 6.4 Hz, 2H), 2.74 (m, 2H), 2.98 (m, 2H), 8.34 (s,
1
3
H), 9.02 (s, 1H). C-NMR (CDCl
3
): 22.32, 22.66, 22.98, 25.23, 25.61 (4CH
CH -triazole), 120.49, 131.31, 133.66, 143.99, 152.87, 153.27
OS
2
cyclohexane, CH ), 44.64
3
(-NCH
2
CH -triazole), 47.11 (-NCH
2
2
2
(C
thiophene and Ctriazole), 158.75 (C=N), 162.17 (C=O). HRMS (EI): m/z calculated for C15
H N
18 5

+
(
M+H) : 316.12; found 316.18.
3
-(2-(1H-Benzo[d]imidazol-1-yl)ethyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-
-1
1
(
3H)-one (5b): Yield: 83%, mp 216 °C. IR (KBr, cm ): 1666 (C=O), 1545 (C=N). H NMR (CDCl
3
):
1
8
2
1
.88 (m, 4H), 2.08 (s, 3H), 4.45 (t, J = 6.4 Hz, 2H), 4.69 (t, J = 6.4 Hz, 2H), 2.77 (m, 2H), 3.03 (m, 2H),
1
3
.20 (s, 1H), 7.37 (m, 2H), 7.53 (m, 1H), 7.82 (m, 1H). C-NMR (CDCl
3
): 22.33, 22.67, 23.00, 25.26,
CH -imidazole), 109.24,
5.66 (4CH cyclohexane, CH ), 42.69 (-NCH CH -imidazole), 44.61(-NCH
2
3
2
2
2
2
20.72, 122.95, 123.86, 124.41, 131.35, 133.76, 152.83 (Cthiophene and Cimidazole), 158.72 (C=N), 161.92
+
(C=O). HRMS (EI): m/z calculated for C20
H
21
N
4
OS (M+H) : 365.14, found 365.21.
3
2
-(2-(2-Methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)-thiazolidine-
-1
,4-dione (5c): Yield: 68%, mp 176 °C. IR (KBr, cm ): 1739, 1701 and 1660 (C=O), 1546 (C=N).
1H-NMR (CDCl
H), 2.93 (m, 2H), 3.63 (s, 2H). C-NMR (CDCl
CH ), 36.59 (CH ꢀthiazolidine), 42.37 (-NCH CH
): 1.82 (m, 4H), 2.56 (s, 3H), 4.39 (t, J = 6.4 Hz, 2H), 4.57 (t, J = 6.4 Hz, 2H), 2.72 (m,
3
1
3
2
3
): 22.29, 22.71, 22.96, 25.21, 25.69 (4CH
2
cyclohexane,
3
2
2
2
-thiazoline), 46.84 (-NCH CH -thiazoline), 119.92,
2
2
1
31.17, 133.46, 153.28 (Cthiophene) 158.34 (C=N), 161.51 (C=O), 166.37, 167.90 (2C=O thiazoline).
+
HRMS (EI): m/z calculated for C16
H
18
N
3
O
3
S
2
(M+H) : 364.08; found 364.13.
2-Methyl-3-(2-((2-oxo-2H-chromen-7-yl)oxy)ethyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
-1
1
4
(3H)-one (5d): Yield: 94%, mp 224 °C. IR (KBr, cm ): 1716 and 1660 (C=O), 1544 (C=N). H-NMR
): 1.82 (m, 4H), 2.74 (s, 3H), 4.35 (t, J = 5.2 Hz, 2H), 4.50 (t, J = 5.2 Hz, 2H), 2.70 (m, 2H), 2.95
m, 2H), 6.21 (d, J = 9.2 Hz, 1H), 7.33 (d, J = 12 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 6.76 (s, 1H), 6.78 (d,
(CDCl
3
(
1
3
J = 2.8 Hz, 1H). C-NMR (CDCl
-NCH CH O), 66.16 (-NCH CH O), 101.65, 112.46, 113.12, 113.67, 120.65, 129.00, 131.40, 133.22,
43.26, 154.16, 155.80 (Cthiophene and Cchromenone), 158.72 (C=N), 161.21 (C=O), 161.90 (C=O). HRMS
3
): 22.33, 23.00, 23.52, 25.23, 25.59 (4CH
2
cyclohexane, CH ), 44.00
3
(
2
2
2
2
1
+
(
EI): m/z calculated for C22
H
21
N
2
O
4
S (M+H) : 409.12; found 409.20.
3-(2-(2-(1H-Indol-3-yl)ethoxy)ethyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-
-1
1
one (5e): Yield: 77%, mp 203 °C. IR (KBr, cm ): 3312 (NH), 1658 (C=O), 1541 (C=N). H-NMR
CDCl ): 1.81 (m, 4H), 2.62 (s, 3H), 4.43 (t, J = 5.2 Hz, 2H), 4.60 (t, J = 5.2 Hz, 2H), 3.17 (t, J = 6.4 Hz,
H), 4.33 (t, J = 6.4 Hz, 2H), 2.73 (m, 2H), 2.91 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.4 Hz,
(
3
2
1
2
1
3
H), 7.18 (m, 1H), 7.10 (m, 1H), 7.05 (s, 1H), 8.25 (br s, 1H). C-NMR (CDCl
5.21, 25.57 (4CH cyclohexane, CH ), 28.80 (indole-CH CH O), 46.86 (-NCH
CH O), 62.66 (indole-CH CH O), 111.32, 112.27, 118.86, 119.45, 120.59, 122.17, 122.65,
27.48, 131.25, 133.07, 136.52, 154.41 (Cthiophene and Cindole), 159.51 (C=N), 161.86 (C=O). HRMS (EI):
3
): 22.30, 22.98, 23.53,
2
3
2
2
2
CH O), 60.92
2
(-NCH
2
2
2
2
1

+
m/z calculated for C23
26
H N
3
O
2
S (M+H) : 408.17; found 408.22.
2
-(2-(2-(2-Methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethoxy)ethyl)iso-
-1
indoline-1,3-dione (5f): Yield: 79%, mp 133 °C. IR (KBr, cm ): 1694 and 1660 (C=O), 1545 (C=N).
1H-NMR (CDCl
): 1.85 (m, 4H), 2.66 (s, 3H), 4.53 (t, J = 5.2 Hz, 2H), 4.60 (t, J = 5.2 Hz, 2H), 4.29 (t, J
6.4 Hz, 2H), 4.33 (t, J =6.4 Hz, 2H), 2.74 (m, 2H), 2.90 (m, 2H), 7.84-7.92 (m, 2H), 7.72-7.79 (m, 2H).
13C-NMR (CDCl
): 22.27, 22.93, 23.33, 25.19, 25.76 (4CH cyclohexane, CH ), 43.64
CH O), 46.71 (-NCH CH O), 61.02 (isoindoline-CH CH O), 62.46 (-NCH CH O),
3
=
3
2
3
(
isoindoline-CH
2
2
2
2
2
2
2
2
1
20.42, 123.39, 131.43, 131.98, 133.12, 135.18, 154.37 (Cthiophene and Cisoindoline), 158.13 (C=N), 161.79
+
(C=O). 165.37 (2C=O). HRMS (EI): m/z calculated for C23
H
24
N
3
O
4
S (M+H) : 438.14; found 438.18.
3
-(2-(1H-1,2,4-Triazol-1-yl)ethyl)-2-methyl-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
-1
4
(3H)-one (5g): Yield: 89%, mp 94 °C. IR (KBr, cm ): 3050 (CHarom), 1655 (C=O), 1545 (C=N).
1H-NMR (CDCl
m, 1H) 1.95 (m, 2H), 7.98 (s, 1H), 8.48 (s, 1H), 7.18-7.30 (m, 5H, CHphenyl). C-NMR (CDCl
5.55, 29.49, 32.30, 34.03 (CH and 3CH cyclohexane, CH ), 40.52 (-NCH CH -triazole), 43.68
-NCH CH -triazole), 119.98, 126.19, 126.59, 128.28, 130.76, 132.88, 145.53, 148.27, 154.96 (Cthiophene
triazoleꢀand Cphenyl), 158.69 (C=N), 161.67 (C=O). HRMS (EI): m/z calculated for C21
): 4.65 (t, J = 5.6 Hz, 2H), 4.48 (t, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.83-2.96 (m, 4H), 3.14
3
1
3
(
3
): 21.28,
2
2
3
2
2
(
2
2
,
C
H
22
N
5
OS (M+H)+:
3
92.15; found 392.41.
3
-(2-(1H-Benzo[d]imidazol-1-yl)ethyl)-2-methyl-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
-1
pyrimidin-4(3H)-one (5h): Yield: 77%, mp 163 °C. IR (KBr, cm ): 3042 (CHarom), 1677 (C=O), 1556
1
(
C=N). H-NMR (CDCl
3
): δ = 4.55 (t, J = 5.6 Hz, 2H), 4.47 (t, J = 5.6 Hz, 2H), 2.70 (s, 3H), 2.81-2.98
(m, 4H), 3.11 (m, 1H) 1.89 (m, 2H), 7.20-7.32 (m, 5H, CHphenyl), 8.12 (s, 1H), 7.41 (m, 2H), 7.52 (m, 1H),
1
3
7
4
1
1
.78 (m, 1H). C-NMR (CDCl
3
): δ = 22.18, 24.97, 29.32, 31.98, 34.14 (CH and 3CH
2
cyclohexane, CH ),
3
0.47 (-NCH CH -imidazole), 43.53 (-NCH
2
2
2
CH -imidazole), 120.08, 122.87, 123.93, 124.67, 126.23,
2
26.74, 128.17, 130.41, 132.49, 144.83, 148.37, 155.04 (Cthiophene, Cimidazole and Cphenyl), 158.34 (C=N),
+
61.08 (C=O). HRMS (EI): m/z calculated for C26
H
25
N
4
OS (M+H) : 441.17; found 441.34.
3
-(2-(2-Methyl-4-oxo-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)-
-1
thiazolidine-2,4-dione (5i): Yield: 67%, mp 211 °C. IR (KBr, cm ): 3047 (CHarom), 1730, 1706 and 1678
1
(
C=O), 1547 (C=N). H-NMR (CDCl
3
): 4.41 (t, J = 6.4 Hz, 2H), 4.58 (t, J = 6.4 Hz, 2H), 2.73 (s, 3H),
1
3
2
.80-2.93 (m, 4H), 3.07 (m, 1H), 1.90 (m, 2H), 7.22-7.31 (m, 5H, CHphenyl), 3.66 (s, 2H). C-NMR
CDCl ): 21.32, 25.47, 29.52, 32.27, 33.86 (CH and 3CH cyclohexane, CH ), 36.44 (CH thiazolidine),
0.48 (-NCH CH -thiazolidine), 43.61 (-NCH CH -thiazolidine), 120.03, 126.33, 126.71, 129.04, 130.84,
(
3
2
3
2
4
2
2
2
2

1
32.82, 145.39, 148.19, 154.79 (Cthiophene and Cphenyl), 158.44 (C=N), 161.51 (C=O), 167.32 (2C=O).
+
HRMS (EI): m/z calculated for C22
H
22
N
3
O
3
S
2
(M+H) : 440.11; found 440.17.
2-Methyl-3-(2-((2-oxo-2H-chromen-7-yl)oxy)ethyl)-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
-1
pyrimidin-4(3H)-one (5j): Yield: 92%, mp 189 °C. IR (KBr, cm ): 3055 (CHarom), 1703 and 1656 (C=O),
1
1
547 (C=N). H-NMR (CDCl
3
): 4.57 (t, J = 5.6 Hz, 2H), 4.42 (t, J = 5.6 Hz, 2H), 2.73 (s, 3H), 2.77-2.92
(m, 4H), 3.05 (m, 1H) 1.92 (m, 2H), 7.19-7.31 (m, 5H, CHphenyl), 6.32 (d, J = 9.2 Hz, 1H), 7.37 (d, J = 12
1
3
Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 6.80 (s, 1H), 6.83 (d, J = 3.2 Hz, 1H). C-NMR (CDCl
3
): 22.38, 25.06,
O), 63.03 (-NCH CH O),
20.17, 123.81, 124.71, 126.21, 126.68, 128.88, 131.47, 132.56, 144.27, 150.12, 155.21 (Cthiophene, Cphenyle
2
1
9.17, 32.03, 34.23 (CH and 3CH
2
cyclohexane, CH
3
), 43.62 (-NCH
2
CH
2
2
2
and Cchromenone), 158.37 (C=N), 161.18 (C=O), 162.24 (C=O). HRMS (EI): m/z calculated for
+
C
28
H
25
N
2
O
4
S (M+H) : 485.15; found 485.38.
3
-(2-(2-(1H-Indol-3-yl)ethoxy)ethyl)-2-methyl-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
-1
pyrimidin-4(3H)-one (5k): Yield: 69%, mp 266 °C. IR (KBr, cm ): 3320 (NH), 3037 (CHarom), 1667
1
(
C=O), 1551 (C=N). H-NMR (CDCl
3
): 4.41 (t, J = 5.6 Hz, 2H), 4.62 (t, J = 5.6 Hz, 2H), 3.23 (t, J = 6.4
Hz, 2H), 4.36 (t, J =6.4 Hz, 2H), 2.75 (s, 3H), 2.79-2.91 (m, 4H), 3.02 (m, 1H) 1.88 (m, 2H), 7.20-7.32
(
(
(
m, 5H), 7.58 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.15 (m, 1H), 7.06 (m, 1H), 7.00 (s, 1H), 8.13
1
3
br s, 1H). C-NMR (CDCl
indole-CH CH O), 43.71 (-NCH
23.17, 124.91, 126.18, 126.73, 128.54, 131.52, 132.17, 136.32, 143.13, 152.23, 155.21 (Cthiophene, Cphenyl
3
): 22.35, 25.19, 29.21, 32.15, 34.13 (CH and 3CH
2
cyclohexane, CH
3
), 30.63
2
2
2
CH O), 61.18 (-NCH CH O), 62.93 (indole-CH
2
2
2
2
CH O), 120.33,
2
1
+
and Cindole), 158.22 (C=N), 160.83 (C=O). HRMS (EI); m/z calculated for C29
H
30
N
3
O S (M+H) : 484.20;
2
found 484.31.
2-(2-(2-(2-Methyl-4-oxo-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-yl)ethoxy)-
-1
ethyl)-isoindoline-1,3-dione (5l): Yield: 75%, mp 173 °C. IR (KBr, cm ): 2966 and 2873 (CHarom), 1690
1
and 1668 (C=O), 1548 (C=N). H-NMR (CDCl
3
): 4.51 (t, J = 5.2 Hz, 2H), 4.58 (t, J = 5.2 Hz, 2H), 4.31 (t,
J = 6.4 Hz, 2H), 4.37 (t, J =6.4 Hz, 2H), 2.67 (s, 3H), 2.86-2.94 (m, 4H), 3.17 (m, 1H), 1.97 (m, 2H),
1
3
7
.20-7.34 (m, 5H), 7.80-7.88 (m, 2H), 7.71-7.77 (m, 2H). C
-
NMR (CDCl
), 40.62 (isoindoline-CH CH O), 46.91 (-NCH
O), 120.49, 126.60, 126.95, 128.67, 131.04, 132.62, 145.55,
3
): 23.50, 25.91, 29.67, 29.78,
3
2.98 (CH and 3CH
2
cyclohexane, CH
3
2
2
2
CH O), 59.12
2
(
isoindoline-CH
2
CH O), 61.22 (-NCH
2
2
CH
2
1
54.58 (Cthiophene, Cphenyl and Cisoindoline), 157.64 (C=N), 160.69 (C=O), 164.87 (2C=O). HRMS (EI): m/z
+
calculated for C29
H
28
N
3
O
4
S (M+H) : 514.18; found 514.24.

ACKNOWLEDGMENTS
The financial assistant from Tunisian Ministry of Higher Education and Scientific Research is
acknowledgedwith thanks. Thanks are due to Dr. Ali Samarat (Department of Chemistry, Faculty of
Sciences of Bizerta) for valuable discussions and his encouragement.
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