Synthesis of some thienopyrimidine derivatives

Article abstract of DOI:10.3390/11070498

Thioxothienopyrimidinones, alkylthio- and arylalkylthiothienopyrimidinones, thienopyrimidinones, thienopyrimidines a thienopyrimidinedione and a thienotriazolopyrimidinone were prepared from 2-amino-3-carboethoxy-4,5- disubstituted thiophenes and 2-amino-

Full text of DOI:10.3390/11070498

Molecules 2006, 11, 498-513
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
Synthesis of Some Thienopyrimidine Derivatives
Fatma E. M. El-Baih 1,*, Hanan A. S. Al-Blowy 1 and Hassan M. Al-Hazimi 2
1
Women Students-Medical Studies & Sciences Sections, Chemistry Department, College of Science,
King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia. Tel.: (+966-1) 477-2245, Fax:
(+966-1) 477-2245.
2
Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451,
Saudi Arabia. Tel.: (+966-1) 467-5905, Fax: (+966-1) 467-5992. E-mail: hhazimi@ksu.edu.sa
* Author to whom correspondence should be addressed; E-mail: zahraa205@yahoo.com
Received: 12 June 2006; in revised form: 28 June 2006 / Accepted: 2 July 2006 / Published: 5 July
2006
Abstract: Thioxothienopyrimidinones, alkylthio- and arylalkylthiothienopyrimidinones,
thienopyrimidinones, thienopyrimidines a thienopyrimidinedione and a thienotriazolo-
pyrimidinone were prepared from 2-amino-3-carboethoxy-4,5-disubstituted thiophenes
and 2-amino-3-cyano-4,5-disubstituted thiophenes via reactions with different reagents.
Keywords: Thioxothienopyrimidinones, alkyl- and arylalkylthiothienopyrimidinones,
thienopyrimidinones, thienopyrimidines, thienopyrimidinediones, thienotriazolo-
pyrimidinones.
Introduction
Many thienopyrimidines are found to exhibit a variety of biological activities, including
antiinflammatory [1,2], antimicrobial [3] and analgesic [4] properties, inhibition of cancer cell
proliferation [5], antagonism of α1 adrenoceptors [6] and prevention of cartilage destruction in articular
diseases [7]. In continuation with our previous work on the title compounds [8,9], we report herein the
synthesis of a series of novel thienopyrimidine derivatives.

Molecules 2006, 11
499
Results and Discussion
The starting materials, namely 2-amino-3-ethoxycarbonyl-4,5-disubstituted thiophenes 1a-c and 2-
amino-3-cyano-4,5-disubstituted thiophenes 1d,e were prepared following the corresponding literature
procedures [10-12]. Thienylthiourea derivatives 2a-h were prepared by condensation of the amino
esters 1a-c with alkyl or aryl isothiocyanates, either by heating at reflux or under microwave
irradiation [8, 9, 13]; the latter method afforded higher yields of the desired products in a shorter time.
Scheme 1
R1 R2
R3
O
R3
S
a (CH2)4
b (CH2)4
c (CH2)4
C6H5
p -Cl-C6H4
(CH2)3CH3
R1
R1
COOC2H5
N
vi
(1b,c)
N
d (CH2)2N(CH3)CH2 p -Cl-C6H4
e (CH2)2N(CH3)CH2 (CH2)3CH3
R2
R2
NH2
S
S
H
4a-g
1a-c
R1 R2
f (CH2)5
g (CH2)5
C6H5
p -Cl-C6H4
a (CH2)4
b (CH2)2N(CH3)CH2
c (CH2)5
v
(3a-c, e-h)
i, ii or iii
O
R3
R1
COOC2H5
R1
N
iv
+
-
R2
NHC-NHR3
S K
S
N
R2
S
2a-h
S
3a-h
(3a,d,h)
R1 R2
R3
vii
O
a (CH2)4
b (CH2)4
c (CH2)4
C6H5
p -Cl-C6H4
(CH2)3CH3
R3
R1
N
d (CH2)2N(CH3)CH2 C6H5
e (CH2)2N(CH3)CH2 p -Cl-C6H4
f (CH2)2N(CH3)CH2 (CH2)3CH3
S-R
N
R2
S
g (CH2)5
h (CH2)5
C6H5
p -Cl-C6H4
5a-c
R1 R2
a (CH2)4
R3
R
C6H5
(CH2)3CH3
CH3
b (CH2)2N(CH3)CH2 C6H5
c (CH2)5
p -Cl-C6H4 CH2C6H5
i) R3NCS, EtOH, reflux, 1-4h
ii) R3NCS, microwave (MW), 45 sec.
v) H2O, HCl, r.t.
vi) p -Cl-C6H4NCS, acetonitrile, reflux, 20h
iii) phenylthiourea, EtOH, microwave (MW), 20 sec. vii) R-X, EtOH, reflux, 1-8h
iv) KOH, EtOH, reflux, 2-6h

Molecules 2006, 11
500
Compounds 2a,d were also prepared by condensation of the amino esters 1a,b with phenylthiourea
under microwave irradiation. Cyclization of 2a-h using alcoholic KOH gave the monopotassium salts
of the corresponding 3-substituted-2-thioxo-4,5-disubstituted-thieno[2,3-d]pyrimidin-4-ones 3a-h.
2-Thioxo derivatives 4a-g were prepared either from the appropriate potassium salts 3 by acidification
or from the amino ester derivatives 1a-c via condensation with aryl isothiocyanates [14, 15].
Alkylation of 3a,d,h with alkyl halides gave 2-alkylthio-derivatives 5a-c.
Condensation of the amino esters 1a,c with ethyl chloroformate gave the carbamate derivatives 6a,b,
which were fused with p-chlorobenzylamine at 230-240°C to afford the dione derivative 7 [16]. The
thienopyrimidinone derivatives 8a,b were prepared by cyclization of the corresponding amino ester
with formamide. Nucleophilic aromatic substitution with POCl3 was carried out on 8a to give the 4-
chlorothienopyrimidine derivative 9. Further substitution with an aromatic amine was carried out on
this chloro derivative 9 to yield the 4-anilino derivative 10 (Scheme 2). The structures of compounds
1-10 were confirmed from their IR, 1H-NMR, 13C-NMR and MS spectral data.
Scheme 2
O
R1
COOC2H5
N
Cl
O
ii
N
R2
NHCOOC2H5
S
S
H
R1 R2
7
a (CH2)4
b (CH2)5
6
i
Cl
O
R1
COOC2H5
H
R1
N
N
iii
iv
R2
NH2
N
S
N
R2
S
v
S
R1 R2
9
R1 R2
1
a
c
(CH2)4
(CH2)5
a (CH )
8
2 4
b (CH2)5
CF3
HN
N
N
S
10
i) ClCO2CH2CH3, reflux, 3h
ii) p -Chlorobenzylamine, fusion, 230-240oC, 8h
iv) POCl3, reflux, 15h
v) 3-CF3C6H4NH2, reflux, 3h
iii) HCONH2, reflux, 1.5h

Molecules 2006, 11
501
Substitution of the mercapto group in 4a,d by hydrazine hydrate afforded the 2-hydrazino
derivative 11 which was then cyclized by glacial acetic acid to give the triazolo derivative 12 [17, 18];
the latter compound is sparingly soluble in CDCl3 and DMSO-d6, precluding the use of 13C-NMR
spectroscopy as a characterization tool. Oxidation of 4a,d by iodine (Scheme 3) gave the disulfides
13a,b [19]. The structures of compounds 11-13 were also confirmed by various spectroscopic
techniques.
Scheme 3
O
O
p -Cl
C6H4-
R1
N
N - R3
i
NHNH2
S
(4b)
N
N
R2
S
S
H
4
11
(4a, d)
iii
ii
O
O
O
R3
p -Cl
C6H4-
R1
R1
N - R3
N
N
S - S
N
N
N
N
R2
N
R2
S
S
S
R1 R2
R3
H3C
12
13a, b
a (CH2)4
C6H5
b (CH2)2N(CH3)CH2 p -Cl-C6H4
i) N2H4.H2O, pyridine, reflux, 15h
ii) gla. AcOH, reflux, 18h
iii) NaOH (10%), KI, Iodine, r.t.
iv) POCl3 / PCl5, reflux,10h
Treatment of 1d,e with triethyl orthoformate followed by ethylenediamine, yielded the 3-amino-
ethyl-4-imino-derivatives 14a,b [20]. Compounds 13b and 14a,b could only be identified by their IR
and MS spectra, as they are insoluble in the common solvents used in NMR. An attempt to prepare 2-
amino-4,5-dimethyl-3-(4,5-dihydro-1H-2-imidazolyl)thiophene (15) following a published procedure
[21], by reacting 1d with ethylenediamine and carbon disulfide did not yield the expected product 15
and instead the intermediate 16 was obtained (Scheme 4). This intermediate was insoluble in the
common solvents used for NMR measurements; but it could be identified by its IR spectrum, which
revealed the expected C=S absorption at 1207 cm-1, and by its MS spectral data (the general
fragmentation patterns proposed for 16 are shown in Scheme 5). Attempts were also made to prepare
2-methyl-4-methoxythienopyrimidine 17 by reacting 1d,e with acetyl chloride followed with methanol
according to a published procedure [20], however, the target compound was not obtained and only the
starting material was recovered.

Molecules 2006, 11
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Scheme 4
NH
MeO
N
R1
R1
R1
N
N - (CH2)2-NH2
iii
ii
i
CH3
N
R2
N
R2
R2
NH2
S
S
S
14a, b
17
R1 , R2
CH3, CH3
(CH2)5
(Id)
ii
S
Id
Ie
N
HN
N
H3C
N
H
NH2
H3C
S
H
H3C
NH2
H3C
NH2
S
S
15
16
ii) a: NH2(CH2)2NH2; b: CS2 / 100oC, 8h
i) a: TEOF, reflux, 4h ; b: NH2(CH2)2NH2,100oC, 7h
iii) a: CH3COCl; b: CH3OH, K2CO3
Scheme 5
NH
S
+.
NH
S
+
H3C
H3C
CH2
S
N
NH2
H
S
N
H
H3C
NH2
S
H3C
NH2
S
m/z = 272 (100%)
-NH3
.
C10H16N4S3
C10H14N3S3
+H
+
fission at c
NH2
S=C=N
NH
S
+
NH3
.
c
H3C
a
b
m/z = 102 (40%)
-2H
S
N
C3H6N2S
H
fission at a
H3C
NH2
.
S
+
-H
H
N
m/z = 289 (0.2%)
HN
S
NH2
C10H17N4S3
-H2S
S
.
fission at b
-H
+.
.
m/z = 162 (58%)
+H
HN
C4H8N3S2
H3C
S
NH2
S
N
+
NH3
N
H3C
H
S
HS
N
m/z = 254 (37%)
H
C10H14N4S2
m/z = 137 (35%)
.
C3H9N2S2
-CH3
.
+2H
HN
+.
HN
H3C
S
+
NH3
H3C
S
-NH3
N
N
H
N=C=CH2
.
S
N
-3H
S
m/z = 241 (5%)
m/z = 221 (34%)
C9H13N4S2
C9H7N3S2

Molecules 2006, 11
503
Experimental
General
Melting points were determined using an Electrothermal IA9000 series digital capillary melting
point apparatus and are uncorrected. IR spectra were obtained as KBr discs on a 1000-Perkin Elmer
1
FT-IR spectrophotometer. H- and 13C-NMR spectra were recorded on a JEOL ECP-400 NMR in
CDCl3 (or DMSO-d6) using TMS as an internal standard. Chemical shifts are given in ppm on the δ
scale and coupling constants (J) are given in Hz. Electron impact (EI) MS spectra were acquired with
the aid of a Shimadzu GCMSQP5050A spectrometer, equipped with a 30 m x 0.25 mm DB-1 glass
column, operating with an ionization energy of 70 eV, at the Chemistry Department, College of
Science, King Saud University. Compounds 2a-h were synthesized using the reported methods [8, 9,
13], or in the case of particular examples, by the methods described below.
Method A: Synthesis of 2d:
A mixture of 1b (0.5 g, 2 mmol) and phenyl isothiocyanate (0.27 g, 2 mmol) was placed in a 50
mL beaker covered with a watch glass and then irradiated with microwaves (600 W) for 45 seconds.
The cold reaction mixture was treated with ethanol and the solid product was filtered off and
recrystallized.
Method B: Synthesis of 2a,d:
A mixture of 1a,b (2 mmol), phenylthiourea (2 mmol) and 5 drops of dry ethanol was placed in a
50 mL beaker, covered with a watch glass, and was then irradiated with microwave (800 W) for 20
seconds. The cold reaction mixture was treated with crushed ice; the solid product was filtered, dried
and recrystallized.
3-Ethoxycarbonyl-2-(3-phenylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene (2a): Fine pale yellow
needles, m.p. 191-193°C (from ethanol); Yield 64%; IR (cm-1): 3416, 3179 (2NH), 1656 (C=O), 1195
1
(C=S); H-NMR (DMSO-d6): 1.30 (3H, t, J = 7.1, CH2CH3), 1.70-1.86 (4H, m, 2CH2 at C-5, C-6),
2.67-2.80 (4H, m, 2CH2 at C-4, C-7), 4.52 (2H, q, J = 7.1, CH2CH3), 7.29-7.33 (2H, m, H-2`, H-6`),
13
7.52-7.56 (3H, m, H-3`, H-4`, H-5`), 10.21 (1H, br. s, NH), 12.25 (1H, br. s, NH); C-NMR: 14.31,
60.75 (Et carbons), 22.09, 23.51, 24.43, 26.42 (aliphatic ring sp3 carbons), 113.02, 121.32, 126.94,
127.11, 130.91, 133.15, 149.85, 135.23 (sp2 carbons), 166.73 (C=O), 176.25 (C=S).
3-Ethoxycarbonyl-2-[3-(4-chlorophenyl)thioureido]-4,5,6,7-tetrahydrobenzo[b]thiophene (2b): Color-
less needles, m.p. 221-223°C (from ethanol); Yield 70%; IR (cm-1): 3442, 3196 (2NH), 1663 (C=O),
1198 (C=S); 1H-NMR (DMSO-d6): 1.27 (3H, t, J = 7.3, CH2CH3), 1.68-1.69 (4H, m, 2CH2 at C-5, C-
6), 2.51-2.55 (2H, m, CH2 at C-4), 2.67-2.68 (2H, m, CH2 at C-7), 4.18 (2H, q, J = 7.3, CH2CH3), 7.23
(2H, d, J = 8.8, H-2`, H-6`), 7.41 (2H, d, J = 8.8, H-3`, H-5`), 10.53 (1H, br. s, NH), 12.02 (1H, br. s,
NH); 13C-NMR: 14.37, 60.49 (Et carbons), 22.97, 23.04, 24.34, 26.43 (aliphatic ring sp3 carbons),

Molecules 2006, 11
504
112.23, 126.24, 128.93, 130.58, 137.24 150.42, 161.32, 125.71, (sp2 carbons), 166.66 (C=O), 176.18
(C=S).
2-(3-Butylthioureido)-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (2c): Fine pale yellow
needles, m.p. 123-125°C (from ethanol); Yield 59%; IR (cm-1): 3429, 3230 (2NH), 1655 (C=O), 1175
1
(C=S); H-NMR (CDCl3): 0.93 (3H, t, J = 8.0, CH2CH2CH3), 1.35 (3H, t, J = 7.1, OCH2CH3), 1.40
(2H, sext., J = 8.0, CH2CH2CH3), 1.63 (2H, quint., J = 8.0, CH2CH2CH2), 1.72-1.78 (4H, m, 2CH2 at
C-5, C-6), 2.56-2.61 (2H, m, CH2 at C-4), 2.71-2.76 (2H, m, CH2 at C-7), 3.45 (2H, br peak,
NHCH2CH2), 4.30 (2H, q, J = 7.1, OCH2CH3), 6.44 (1H, br. s, NH), 12.10 (1H, br. s, NH); 13C-NMR:
14.42, 60.71 (Et carbons), 13.81, 20.11, 30.73, 44.15 (butyl group), 22.92, 23.15, 24.42, 26.51
(aliphatic ring sp3 carbons) 112.01, 126.32, 130.67, 151.43 (thiophene carbons), 167.25 (C=O), 177.03
(C=S).
3-Ethoxycarbonyl-6-methyl-2-(3-phenylthioureido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2d): Fine
yellow needles, m.p. 186-188°C (from ethanol/chloroform); Yield 60%; IR (cm-1): 3467, 3175 (2NH),
1658 (C=O), 1195 (C=S); 1H-NMR (CDCl3): 1.24 (3H, t, J = 7.2, CH2CH3), 2.46 (3H, s, CH3N), 2.66
(2H, t, J = 5.9, CH2 at C-4), 2.85 (2H, t, J = 5.8, CH2 at C-5), 3.49 (2H, s, CH2 at C-7), 4.12 (2H, q, J =
7.2, CH2CH3), 7.31-7.36 (3H, m, H-2`,H-4` ,H-6`), 7.47 (2H, t, J =7.4, H-3`,H-5`), 8.01 (1H, br. s,
13
NH), 12.12 (1H, br. s, NH); C-NMR: 14.25, 60.56 (Et carbons), 45.63 (CH3N), 52.50, 26.88, 53.24
(aliphatic ring sp3 carbons), 112.54, 124.07, 125.80, 127.95, 129.04, 130.13, 135.81 150.52, (sp2
carbons), 166.14 (C=O), 176.29 (C=S); MS: m/z (%) 375 [M+] (96) (C18H21N3O2S2), 332 [M-CH3-
C2H5] (18), 282 [M-C6H5-CH3-H] (13), 239 [M-C6H5NHCS] (100), 166 [M-C6H5NHCS-C2H5OH-
C2H4+H] (36).
3-Ethoxycarbonyl-2-[3-(4-chlorophenyl)-6-methylthioureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
(2e): Fine yellow cubes, m.p. 206-208°C (from ethanol/ chloroform); Yield 60%; IR (cm-1): 3415,
3180 (2NH), 1659 (C=O), 1195 (C=S); 1H-NMR (CDCl3): 1.27 (3H, t, J = 7.2, CH2CH3), 2.46 (3H, s,
CH3N), 2.67 (2H, t, J = 5.7, CH2 at C-4), 2.86 (2H, t, J = 5.7, CH2 at C-5), 3.50 (2H, s, CH2 at C-7),
4.18 (2H, q, J = 7.2, CH2CH3), 7.26 (2H, d, J = 8.8, H-2`, H-6`), 7.41(2H, d, J = 8.8, H-3`, H-5`), 7.89
13
(1H, br. s, NH), 12.21 (1H, br. s, NH); C-NMR: 14.25, 60.78 (Et carbons), 45.63 (CH3N), 26.88,
52.46, 53.21 (aliphatic ring sp3 carbons), 112.46, 123.91, 126.92, 129.04, 130.18, 133.17, 134.53,
150.27 (sp2 carbons), 166.43 (C=O), 176.17 (C=S); MS: m/z (%) 409 [M+] (59) (C18H2035ClN3O2S2),
411 [M+2] (22) (C18H2037ClN3O2S2), 366 [M-CH3-C2H4] (12), 282 [M-ClC6H4-CH3–H] (37), 239 [M-
ClC6H4NHCS] (91), 169 [M-ClC6H4NHCS-C2H5OH-C2H4+3H] (58).
2-(3-Butylthioureido)-3-ethoxycarbonyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2f): Fine
red needles, m.p. 224-226°C (from ethanol/chloroform);Yield 60%; IR (cm-1): 3434, 3162 (2NH),
1
1650 (C=O), 1169 (C=S); H-NMR (DMSO-d6): 0.89 (3H, t, J = 8.0, CH2CH2CH3), 1.09 (3H, t, J =
7.3, OCH2CH3), 1.31 (2H, sext., J = 7.3, CH2CH2CH3), 1.62 (2H, quint., J = 7.3, CH2CH2CH2), 2.41
(3H, s, CH3N), 2.68 (2H, t, J = 5.9, CH2 at C-4), 2.91-2.95 (2H, m, CH2 at C-5), 3.47 (2H, s, CH2 at C-
7), 3.52 (2H, t, J = 7.3, NHCH2CH2), 4.31 (2H, q, J = 7.1, OCH2CH3), 8.85 (1H, br. s, NH), 9.29 (1H,
br. s, NH); 13C-NMR: 18.59, 57.36 (Et carbons), 13.93, 20.29, 28.69, 45.98 (Bu carbons), 45.28
(CH3N), 25.47, 51.59, 52.97 (aliphatic ring sp3 carbons), 116.02, 125.17, 129.89, 149.62 (thiophene

Molecules 2006, 11
505
carbons), 157.19 (C=O), 174.25 (C=S); MS: m/z (%) 355 [M+] (12) (C16H25N3O2S2), 309 [M-C2H5OH]
(100), 252 [M-C4H9-C2H5OH] (13), 210 [M-C4H9NHCS-2CH3+H] (35).
General procedure for the preparation of 3a-h:
A mixture of the compounds 2a-h (13.5 mmol) and potassium hydroxide (0.76 g, 13.5 mmol) in
absolute ethanol (55 mL) was heated under reflux with stirring for 1 h. The suspension was filtered
while hot and the solid was washed with hot absolute ethanol to give 3a-h.
General procedure for the synthesis of 4a-g: Method A:
A suspension of potassium salts of 3a-c,e-h in water (50 mL) was acidified with concentrated
hydrochloric acid and stirred at room temperature for 30 min. The solid was collected by filtration,
washed with water and recrystallized from ethanol to give 4a-g.
Method B: Synthesis of 4d,g.
A mixture of 1b,c (10 mmol) and the appropriate isothiocyanate (10 mmol) in acetonitrile (30 mL)
was heated under reflux for 15 h in the presence of anhydrous potassium carbonate (1.4 g). The
reaction mixture was then cooled, filtered, diluted with water (10 mL) and neutralized with 2M
hydrochloric acid. The product obtained was filtered, washed with water, dried and recrystallized from
ethanol to give 4d,g.
Monopotassium salt of 3-phenyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-benzo[4,5]thieno[2,3-d]-
pyrimidin-4-one (3a) and its 2-thioxo derivative 4a: Yields: 53% (3a) and 73% (4a), respectively;
1
Compound 4a: white powder, m.p. 259-261°C; IR (cm-1): 3413 (NH), 1705 (C=O), 1218 (C=S); H-
NMR (CDCl3): 1.77-1.85 (4H, m, 2CH2 at C-6, C-7), 2.63-2.68 (2H, m, CH2 at C-5), 2.84-2.91 (2H, m,
CH2 at C-8), 7.24-7.26 (2H, m, H-2`, H-6`), 7.45-7.57 (3H, m, H-3`, H-4`, H-5`), 12.19 (1H, br. s, NH);
13C-NMR: 21.96, 22.96, 24.72, 25.14 (aliphatic ring sp3 carbons), 117.53, 128.52, 129.07, 129.49,
129.70, 132.64, 138.56, 148.51 (sp2 carbons), 157.37 (C=O), 174.93 (C=S); MS: m/z (%) 314 [M+]
(100) (C16H14N2OS2), 179 [M-C6H5NCS] (89), 151 [M-C6H5NCS-C2H4] (35).
Monopotassium salt of 3-(4-chlorophenyl)-2-thioxo-2,3,5,6,7,8-hexahydro-1H-benzo[4,5]thieno[2,3-
d]-pyrimidin-4-one (3b) and its 2-thioxo derivative 4b: Yields: 75% (3b) and 89% (4b), respectively;
1
Compound 4b: white scales, m.p. 289-292°C; IR (cm-1): 3129 (NH), 1706 (C=O), 1219 (C=S); H-
NMR (DMSO-d6): 1.70-1.71 (2H, m, CH2 at C-6), 1.77-1.78 (2H, m, CH2 at C-7), 2.66-2.70 (2H, m,
CH2 at C-5), 2.71-2.75 (2H, m, CH2 at C-8), 7.28 (2H, d, J =8.1, H-2`, H-6`), 7.52 (2H, d, J = 8.1, H-
13
3`, H-5`), 13.71 (1H, br. s, NH); C-NMR: 22.10, 23.02, 24.52, 25.38 (aliphatic ring sp3 carbons),
116.67, 128.97, 129.57, 131.62, 131.69, 133.17, 138.81, 149.92 (sp2 carbons), 157.38 (C=O), 174.88
(C=S); MS: m/z (%) 348 [M+] (86) (C16H1335ClN2OS2), 350 [M+2] (35) (C16H1337ClN2OS2), 179 [M-
ClC6H4NCS] (100), 151 [M-ClC6H4NCS-C2H4] (38).

Molecules 2006, 11
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Monopotassium salt of 3-butyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-benzo[4,5]thieno[2,3-d]pyrimidin-
4-one (3c) and its 2-thioxo derivative 4c: Yields: 40% (3c) and 78% (4c), respectively; Compound 4c:
1
white scales, m.p. 234-236°C; IR (cm-1): 3254 (NH), 1689 (C=O), 1220 (C=S); H-NMR (CDCl3):
0.97 (3H, t, J = 7.3, CH2CH3), 1.42 (2H, sext., J =7.3, CH2CH2CH3), 1.71-1.87 (6H, m, 3CH2 at C-6,
C-7, C-2`), 2.66 (2H, t, J = 5.8, CH2 at C-5), 2.91 (2H, t, J = 5.8, CH2 at C-8), 4.43 (2H, t, J = 7.7,
NCH2CH2), 12.31 (1H, br. s, NH); 13C-NMR: 13.88, 20.33, 28.82, 46.59, (Bu carbons), 21.99, 22.97,
24.76, 25.31 (aliphatic ring sp3 carbons), 117.31, 129.32 132.29, 147.89 (thiophene carbons), 156.85
(C=O), 173.52 (C=S); MS: m/z (%) 294 [M+] (71) (C16H18N2OS2), 261 [M-SH] (100), 238 [M-
C4H9+H] (40), 179 [M-C4H9NCS] (75), 151 [M-C4H9NCS-C2H4] (29).
Monopotassium salt of 7-methyl-3-phenyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrido[3`,4`:5,4]-
1
thieno[2,3-d]pyrimidin-4-one (3d): Yield 45%; IR (cm-1): 1650 (C=O); H-NMR (DMSO-d6): 2.31
(3H, s, CH3N), 3.21 (2H, t, J = 5.9, CH2 at C-5), 3.38-3.42 (2H, m, CH2 at C-6), 4.33 (2H, s, CH2 at C-
8), 7.31-7.33 (3H, m, H-2`, H-4`, H-6`), 7.45-7.52 (2H, t, J =7.8, H-3`, H-5`); 13C-NMR: 46.44
(CH3N), 26.24, 53.50, 54.31 (aliphatic ring sp3 carbons), 118.79,122.37, 128.37, 129.83, 131.45,
131.65, 142.13, 157.74, (sp2 carbons), 165.68 (C=O), 176.23 (C=S).
Monopotassium salt of 3-(4-chloro-phenyl)-7-methyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrido-
[3`,4`:5,4]thieno[2,3-d]pyrimidin-4-one (3e) and its 2-thioxo derivative 4d: Yields: 85% (3e) and 89%
(4d), respectively; Compound 4d: pale orange scales, m.p. 256-258°C; IR (cm-1): 3137 (NH), 1691
1
(C=O), 1213 (C=S); H-NMR (DMSO-d6): 2.88 (3H, s, CH3N), 2.98-3.12 (2H, m, CH2 at C-5), 3.36-
3.46 (2H, m, CH2 at C-6), 4.39 (2H, s, CH2 at C-8), 7.29 (2H, d, J = 8.1, H-2`, H-6`), 7.53 (2H, d, J =
13
8.1, H-3`, H-5`), 11.18 (1H, br. s, NH); C-NMR: 42.22 (CH3N), 22.79, 49.89, 50.55 (aliphatic ring
sp3 carbons), 115.56, 120.55, 128.83, 129.64, 131.56, 133.31, 138.57, 151.80, (sp2 carbons), 157.32
(C=O), 175.38 (C=S); MS: m/z (%) 363 [M+] (84) (C16H1435ClN3OS2), 365 [M+2] (35)
(C16H1437ClN3OS2), 193 [M-ClC6H4NCS] (21), 151 [M-ClC6H4NCS-C2H4-CH3] (100).
Monopotassium salt of 7-methyl-3-butyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrido[3`,4`:5,4]thieno-
[2,3-d]pyrimidin-4-one (3f) and its 2-thioxo derivative 4e: Yields: 51% (3f) and 45% (4e), respectively;
1
Compound 4e: yellow scales, m.p. 297-299°C; IR (cm-1): 3176 (NH), 1687 (C=O), 1200 (C=S); H-
NMR (DMSO-d6): 0.92 (3H, t, J = 7.3, CH2CH3), 1.32 (2H, sext., J =7.3, CH2CH2CH3), 1.62 (2H,
quint., J =7.3, CH2CH2CH2),4.41 (2H, t, J = 7.7 NCH2CH2 ), 2.49 (3H, s, CH3N), 2.84-2.89 (2H, m,
13
CH2 at C-5), 3.14-3.20 (2H, m, CH2 at C-6 ), 3.34 (2H s,, CH2 at C-8), 13.71 (1H, br. s, NH); C-
NMR: 14.47, 20.25, 28.69, 45.93 (Bu carbons), 45.42 (CH3N), 26.81, 52.54, 53.22 (aliphatic ring sp3
carbons), 114.42, 124.98, 130.76, 149.81 (thiophene carbons), 156.38 (C=O), 175.94 (C=S); MS: m/z
(%) 309 [M+] (100) (C14H19N3OS2), 193 [M-C4H9NCS-H] (15), 151 [M-C4H9NCS-C2H4-CH3] (14).
Monopotassium salt of 3-phenyl-2-thioxo-1,2,3,5,6,7,8,9-octahydrocyclohepta[4,5]thieno[2,3-d]-
pyrimidin-4-one (3g) and its 2-thioxo derivative 4f: Yields: 42% (3g) and 83% (4f); Compound 4f:
1
pale yellow powder, m.p. 306-308°C; IR (cm-1): 3141 (NH), 1698 (C=O), 1221 (C=S); H-NMR
(DMSO-d6): 1.54-1.62 (2CH2 m, 4H at C-6, C-7), 1.81 (2H, br. peak, CH2 at C-8), 2.76 (2H, br. peak,
CH2 at C-5), 3.09 (2H, br. peak, CH2 at C-9), 7.20-7.21 (2H, d, J = 7.1, H-2`, H-6`), 7.38 (1H, t, J =
7.3, H-4`), 7.45 (2H, t, J = 7.3, H-3`, H-5`), 13.57 (1H, br. s, NH); 13C-NMR: 27.17 (2C), 27.86, 28.95,

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32.26 (aliphatic ring sp3 carbons), 117.23, 128.47, 129.38, 129.58, 132.66, 137.20, 139.99, 148.57 (sp2
carbons), 157.94 (C=O), 174.87 (C=S); MS: m/z (%) 328 [M+] (100) (C17H16N2OS2), 193 [M-
C6H5NCS] (39), 151 [M-C6H5NCS-C2H4-NH+H] (6).
Monopotassium salt of 3-(4-chlorophenyl)-2-thioxo-1,2,3,5,6,7,8,9-octahydrocyclohepta[4,5]thieno-
[2,3-d]pyrimidin-4-one (3h) and its 2-thioxo derivative 4g: Yields: 88% (3h) and 85% (4g),
respectively; Compound 4g: white scales, m.p. 263-265°C, 3123 (NH), 1710 (C=O), 1220 (C=S); 1H-
NMR (DMSO-d6): 1.53 (2H, br. peak, CH2 at C-7), 1.61 (2H, br. peak, CH2 at C-6), 1.82 (2H, br. peak,
CH2 at C-8), 2.77 (2H, br. peak, CH2 at C-5), 3.08 (2H, br. peak, CH2 at C-9), 7.28 (2H, d, J = 8.8, H-
2`,H-6`), 7.52 (2H, d, J = 8.8, H-3`,H-5`), 13.68 (1H, br. s, NH); 13C-NMR: 27.14 (2C), 27.86, 28.93,
32.33 (aliphatic ring sp3 carbons), 117.20, 129.52, 131.65, 132.79, 133.12, 137.21, 138.95, 148.63 (sp2
carbons), 157.90 (C=O), 174.62 (C=S); MS: m/z (%) 362 [M+] (100) (C17H15 35ClN2OS2), 364 [M+2]
(44) (C17H1537ClN2OS2), 193 [M-ClC6H4NCS] (74), 151 [M-ClC6H4NCS-C2H4-NH+H] (19).
General procedure for synthesis of 5a-c:
A mixture of potassium salt of 3a, d, h (3.6 mmol) and the appropriate alkyl halide (4.32 mmol) in
ethanol (15 mL) was heated under reflux with stirring for 1 h (for compounds 5a,b) and for 8 h (for
compound 5c). The solid obtained was filtered, washed with water, dried and recrystallized from
ethanol/chloroform.
2-Butylthio-3-phenyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (5a): Colorless
1
scales, m.p. 230-232°C; Yield 90%; IR (cm-1): 1689 (C=O); H-NMR (CDCl3): 0.90 (3H, t, J = 7.3,
CH2CH3), 1.39 (sext., 2H, J =7.3, CH2CH2CH3), 1.61 (2H, quint., J =7.3, CH2CH2CH2), 1.79-1.87 (4H,
m, 2CH2 at C-6, C-7), 2.70-2.76 (2H, m, CH2 at C-5), 2.91-2.94 (m, 2H, CH2 at C-8), 3.12 (2H, t, J =
7.3, NCH2CH2), 7.25-7.27 (2H, m, H-2`, H-6`), 7.51-7.53 (3H, m, H-3`, H-4`, H-5`); 13C-NMR: 13.73,
22.04, 30.59, 32.59 (Bu carbons), 22.38, 23.10, 25.17, 25.46 (aliphatic ring sp3 carbons), 119.15,
129.12, 129.76, 129.89, 131.68, 131.74, 136.04, 157.75 (sp2 carbons), 158.69 (C=O), 162.11 (C=S);
MS: m/z (%) 370 [M+] (100) (C20H22N2OS2), 314 [M-C4H9+H] (74), 281 [M-SC4H9] (39), 253 [M-
SC4H9-C2H4] (6), 179 [M-SC4H9-C2H4-C6H5+3H] (79), 151 [M-C4H9-C2H4-C6H5NCS+H] (16).
3-Phenyl-7-methyl-2-methylthio-5,6,7,8-tetrahydro-3H–pyrido[3`,4`:5,4]thieno[2,3-d]pyrimidin-4-one
(5b): Fine yellow needles, m.p. 296-298°C; Yield 75%; IR (cm-1): 1692 (C=O); 1H-NMR (DMSO-d6):
2.45 (3H, s, NCH3), 3.17-3.21 (2H, m, CH2 at C-5), 3.36 (3H, s, SCH3), 3.71 (2H, t, J = 5.9, CH2 at C-
6), 4.75 (2H, s, CH2 at C-8), 7.41-7.42 (2H, m, H-2`, H-6`), 7.55-7.62 (3H, m, H-3`, H-4`, H-5`); 13C-
NMR: 15.93 (SCH3), 51.44 (CH3N), 22.20, 58.51, 60.01 (aliphatic ring sp3 carbons), 117.88, 121.26,
127.43, 129.71, 130.24, 130.63, , 136.02, 157.84 (sp2 carbons), 161.18 (C=O), 163.85 (C=S); MS: m/z
(%) 343 [M+] (88) (C17H17N3OS2), 328 [M-CH3] (47), 300 [M-CH3-C2H4] (100), 253 [M-CH3-C2H4-
SCH3] (83), 193 [M-CH3-C6H5NCS] (6), 150 [M-2CH3-C6H5NCS-C2H4] (27).
2-Benzylthio-3-(4-chloro-phenyl)3,5,6,7,8,9-hexahydrocyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one
1
(5c): Fine colorless needles, m.p. 264-266°C; Yield 88%; IR (cm-1): 1680 (C=O); H-NMR (CDCl3):
1.61-1.74 (4H, m, 2CH2 at C-6, C-7 ), 1.84-1.88 (2H, m, CH2 at C-8), 2.82-2.85 (2H, m, CH2 at C-5),

Molecules 2006, 11
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3.23-3.26(2H, m, CH2 at C-9), 4.33 (2H, s, SCH2Ph), 7.19 (2H, d, J = 8.8, H-2`, H-6`), 7.23-7.34 (5H,
m, Ar-H), 7.46 (d, 2H, J = 8.8, H-3`, H-5`); 13C-NMR: 27.32, 27.78, 27.90, 29.94, 32.69 (aliphatic ring
sp3 carbons), 37.31 (SCH2Ph), 119.70, 127.71, 128.68, 129.44, 130.06, 130.60, 134.33, 135.91, 136.06,
136.60, 137.37, 156.14 (sp2 carbons), 159.04 (C=O), 160.90 (C=S); MS: m/z (%) 452 [M+] (67)
(C24H2135ClN2OS2), 454 [M+2] (30) (C24H2137ClN2OS2), 419 [M-Cl+2H] (29), 361 [M-CH2C6H5] (6),
326 [M-Cl-CH2C6H5] (9), 201 [M-SHCH2C6H5-ClC6H4NH2] (100).
General procedure for synthesis of 6a,b:
A mixture of 1a,c (15.8 mmol) and ethyl chloroformate (40 mL) was refluxed for 3h. After cooling,
the reaction mixture was evaporated under reduced pressure and the residue was recrystallized from
ethanol.
2-Ethoxycarbonylamino-3-ethoxycarbonyl-5,6,7,8-tetrahydrobenzo[b]thiophene (6a): Fine pale brown
needles, m.p. 66-68 °C; Yield 87%; IR (cm-1): 3246 (NH), 1724, 1662 (2C=O); 1H-NMR (DMSO-d6):
1.25 (3H, t, J = 7.3 CH2CH3), 1.28 (3H, t, J = 6.9 CH2CH3), 1.68-1.70 (4H, m, 2CH2 at C-5, C-6),
2.54-2.56 (2H, m, CH2 at C-4), 2.64-2.66 (2H, m, CH2 at C-7), 4.19 (2H, q, J = 7.3 OCH2CH3), 4.23
13
(2H, q, J = 7.3 OCH2CH3), 10.34 (1H, br s, NH); C-NMR: 14.56, 62.59 (Et carbons), 14.78, 60.89
(Et carbons), 22.77, 23.01, 24.27, 26.42 (aliphatic ring sp3 carbons), 111.01, 125.69, 131.32, 148.62
(thiophene carbons), 165.85 (C=O), 152.75 (carbamate C=O); MS: m/z (%) 297 [M+] (100)
(C14H19NO4S), 251 [M-C2H5OH] (89), 223 [M-C2H5COOH] (30), 205 [M-2C2H5OH] (38), 195 [M-
C2H5COOH-C2H4] (10), 179 [M-COOC2H5-C2H5O] (54), 151 [M-COOC2H5-C2H5O-C2H4] (32).
2-Ethoxycarbonylamino-3-ethoxycarbonyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene (6b): Fine
1
pale brown needles, m.p. 78-80 °C; Yield 70%; IR (cm-1): 3241 (NH), 1728, 1662 (2C=O); H-NMR
(DMSO-d6): 1.25 (3H, t, J = 6.9 CH2CH3), 1.28 (3H, t, J = 7.1, CH2CH3), 1.52-1.58 (4H, m, 2CH2 at
C-5, C-6), 1.76-1.78 (2H, m, CH2 at C-7), 2.65-2.69 (2H, m, CH2 at C-4), 2.90-2.93 (2H, m, CH2 at C-
8), 4.18 (2H, q, J = 7.1 OCH2CH3), 4.26 (2H, q, J = 7.4 OCH2CH3), 10.11 (1H, br. s, NH); 13C-NMR:
14.82, 62.40 (Et carbons), 14.53, 61.05 (Et carbons), 27.12, 27.98, 28.14, 28.45, 32.11 (aliphatic ring
sp3 carbons), 116.25, 130.13, 137.03, 145.61 (thiophene carbons), 165.55, (C=O), 153.04 (carbamate
C=O); MS: m/z (%) 311 [M+] (100) (C15H21NO4S), 283 [M-C2H4] (8), 265 [M-C2H5OH] (72), 237 [M-
HCOOC2H5] (26), 219 [M-HCOOC2H5-CH3-3H] (35), 193 [M-COOC2H5-C2H5O] (33), 165 [M-
COOC2H5-C2H5O-C2H4] (17), 151 [M-COOC2H5-C2H5O-C2H4-CH3+H] (7), 139 [M-COOC2H5-
C2H5O-C2H4-HCN+H] (10).
3-(4-Chlorobenzyl)-5,6,7,8-tetrahydro-1H-benzo[4,5]thieno[2,3-d]pyrimidine-2,4-dione (7):
A mixture of 6a (1.2 g, 3.7 mmol) and 4-chlorobenzylamine (1.0 g, 7.1 mmol) was heated to 230-
240 °C for 8 h. After cooling, the crude solid was recrystallized from ethanol/water to give 7 as a
brown powder, m.p.236-238 °C; Yield 60%; IR (cm-1): 3232 (NH), 1724 (C=O at 4 position), 1660
(C=O at 2 position); 1H-NMR (CDCl3): 1.78-1.85 (4H, m, 2 CH2 at C-6, C-7) 2.61-2.63 (2H, m, CH2
at C-5) 2.87-2.89 (2H, m, CH2 at C-8),5.09 (2H, s, NCH2C6H4Cl), 7.23 (2H, d, J = 8.8, H-2`, H-
6`),7.41 (2H, d, J = 8.8, H-3`, H-5`), 10.27 (1H, br. s, NH); 13C-NMR: 22.07, 23.15, 24.59, 25.45

Molecules 2006, 11
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(aliphatic ring sp3 carbons), 43.13 (NCH2 Ar), 113.91, 126.98, 128.57, 130.44, 132.34, 133.84, 135.58,
148.52, (sp2 carbons), 152.41 (C=O at C-2), 158.90 (C=O at C-4); Ms: m/z (%) 346 [M+] (41)
(C17H1537ClN2O2S), 348 [M+2] (17) (C17H1535ClN2O2S), 179 (30) [M-OCNCH2C6H4Cl], 308 (22) [M-
HCl-2H], 221 (61) [M-CH2C6H4Cl], 151 (17) [M-OCNCH2C6H4Cl-CO], 140 (98) [M-C10H8NO2S],
125 (100) [M-C10H9N2O2S].
General procedure for synthesis of 8a,b:
A mixture of 1a,c (2 mmol) and formamide (20 mL) was heated under reflux for 1.5 h, then left to
cool to room temperature overnight. The solid formed was filtered, washed with water, dried and
recrystallized from ethanol.
5,6,7,8-Tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (8a): Fine pale brown needles, m.p.
255-257 °C; Yield 92%; IR (cm-1): 3415 (NH), 1693 (C=O); 1H-NMR (DMSO-d6): 1.73-1.79 (4H, m,
2CH2 at C-6, C-7), 2.71-2.74 (2H, m, CH2 at C-5), 2.85-2.87 (2H, m, CH2 at C-8), 7.99 (1H, s, H-2),
12.29 (1H, br. s, NH); 13C-NMR: 22.32, 23.01, 24.99, 25.89 (aliphatic ring sp3 carbons), 123.23,
131.36, 136.77, 145.39 (thiophene carbons), 158.26 (C-2), 162.97 (C=O); Ms: m/z (%) 206 [M+] (100)
(C10H10N2OS), 191 [M-NH] (36), 178 [M-CO] (91), 165 [M-CONH+2H] (7), 150 [M-CO-C2H4] (7),
136 [M-CONH-HCN] (3).
3,5,6,7,8,9-Hexahydrocyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one (8b): Fine pale brown needles,
m.p. 209-211 °C; Yield 90%; IR (cm-1): 3411 (NH), 1705 (C=O); 1H-NMR (DMSO-d6): 1.53-1.65 (4H,
m, 2CH2 at C-6, C-7), 1.80-1.87 (2H, m, CH2 at C-8), 2.80-2.83 (2H, m, CH2 at C-5), 3.23-3.26 (2H,
13
m, CH2 at C-9) 7.98 (1H, s, H-2), 12.31 (1H, br. s, NH); C-NMR: 27.42, 27.80, 27.86, 29.57, 32.56
(aliphatic ring sp3 carbons), 123.76, 132.15, 137.01,145.07 (thiophene carbons), 158.75 (C-2), 161.39
(C=O); MS: m/z (%) 220 [M+] (100) (C11H12N2OS), 205 [M-NH] (67), 191 [M-CHO] (46), 192 [M-
CO] (48), 178 [M-CONH+H] (23), 165 [M-CO-C2H4+H] (25), 148 [M-HCONH2-HCN] (6).
4-Chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (9):
A mixture of 8a (1 g, 5 mmol) and phosphorus oxychloride (10 mL) was heated under reflux for 15
h. The excess phosphorus oxychloride was removed by distillation under reduced pressure, the residue
treated with dry benzene (5 mL) and the solvent distilled under reduced pressure to remove the last
traces of phosphorus oxychloride. The residue left was triturated with ice and sodium bicarbonate
solution (10 %), the solid thus obtained was collected, washed with water and recrystallized from
1
toluene to give a 48% yield of the title compound 9 as fine pale brown needles, m.p. 90-92 °C; H-
NMR (CDCl3): 1.89-1.91 (4H, m, 2CH2 at C-6, C-7), 2.86-2.87 (2H, m, CH2 at C-5), 3.05-3.06 (2H, m,
CH2 at C-8), 8.68 (1H, s, H-2); 13CNMR: 22.27, 22.50, 26.12, 26.36 (aliphatic ring sp3 carbons),
127.23, 128.91, 139.72, 153.23, 168.89, 151.57 (sp2 carbons); Ms: m/z (%) 224 [M+] (65)
35
37
(C10H9 ClN2S); 226 [M+2] (25) (C10H9 ClN2S), 196 (100) [M-C2H4], 161 (10) [M-HCN-HCl].

Molecules 2006, 11
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4-N-(3-Trifluoromethylphenyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (10):
A mixture of 9 (0.5 g, 2 mmol) and 3-trifluoromethyl aniline (5 g, 40 mmol) was heated under
reflux for 3 h and left overnight. The oily product was treated several times with petroleum ether (b.p.
40-60°C) and the separated solid was washed several times with petroleum ether to give a 15% yield
of compound 10 as a brown powder, m.p. 224-226 °C; IR (cm-1): 3450 (NH); 1H-NMR (CDCl3): 1.91-
2.01 (4H, m, 2CH2 at C-6, C-7), 2.84-2.86 (2H, m, CH2 at C-5), 3.06-3.07 (2H, m, CH2 at C-8), 7.29
(1H, s, H-2`), 7.35 (1H, d, J = 8.1, H-6`), 7.47 (1H, t, J = 7.6, H-5`), 7.89 (1H, d, J = 8.1 , H-4`), 7.95
(1H, br. s, NH); 13C-NMR: 22.41, 22.55, 25.62, 26.58 (aliphatic ring sp3 carbons), 120.51 (CF3),
116.93, 117.69, 117.73, 120.47, 124.22, 124.67, 129.62, 135.78, 139.03, 151.82,, 154.67, 165.66 (sp2
carbons); MS: m/z (%) 349 [M+] (100) (C17H14F3N3S), 334 [M-F+4H] (20), 320 [M-C2H4-H] (10), 304
[M-C2H4-F+2H] (5), 294 [M-3F+2H] (2), 204 [M-C6H4CF3] (16).
3-(4-Chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (11):
A mixture of 4b (1.4 g, 4 mmol) and 99% hydrazine hydrate (4 mL, 80 mmol) in pyridine (20 mL)
was heated under reflux for 15 h. The mixture was evaporated under reduced pressure and the residue
was treated with ethanol. The solid product was filtered and washed several times with ethanol to give
1
a 75% yield of 11 as colorless needles, m.p. 204-204 °C; IR (cm-1): 3488-3272 (NH, NH2); H-NMR
(acetic acid-d4): 1.74-1.86 (4H, m, 2CH2 at C-6, C-7), 2.67-2.68 (2H, m, CH2 at C-5), 2.81-2.83 (2H,
m, CH2 at C-8), 7.38 (1H, br. s, NH), 7.39 (1H, br. s, NH), 7.56 (1H, br. s, NH), 7.43 (2H, d, J = 8.7,
H-2`, H-6`), 7.58 (2H, d, J = 8.7, H-3`, H-5`); MS: m/z (%) 346 [M+] (89) (C16H1535ClN4OS), 348
[M+2] (34) C16H1537ClN4OS), 331 [M-NH2+H] (100), 316 [M-N2H4+2H] (32), 303 [M-NH2+H-C2H4]
(63), 220 [M-NH-C6H4Cl] (22).
4-(4-Chlorophenyl)-1-methyl-6,7,8,9-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,2,4]triazolo[3,4-b]-
pyrimidin-5-one (12):
A mixture of 11 (1.4 g, 4 mmol) and glacial acetic acid (15 mL) was heated under reflux with
stirring for 8 h. The reaction mixture was allowed to cool to room temperature and was poured into
water (50 mL). The formed solid was collected by filtration, washed with ethanol, dried and
recrystallized from ethanol to give 12 as colorless fine needles, m.p. 300-300 °C; Yield 72%; IR (cm-1):
1676 (C=O); 1H-NMR (CDCl3): 1.83-1.91 (4H, m, 2CH2 at C-7, C-8), 2.79- 2.81 (5H, m, CH3, CH2 at
C-6), 3.00 (2H, t, J = 6.2, CH2 at C-9), 7.37 (2H, d, J = 8.8, H-2`, H-6`), 7.51 (2H, d, J = 8.8, H-3`, H-
5`); MS: m/z (%) 370 [M+] (100) (C18H1535ClN4OS), 372 [M+2] (38) C18H1537ClN4OS), 355 [M-CH3]
(4), 328 [M-CH3-C2H4+H] (22).
General procedure for synthesis of 13a,b:
A solution of iodine (50.76 g, 20 mmol), in 5% KI solution (100 mL) was added dropwise with
stirring to a solution of 4a,d (10 mmol) in 10% aqueous sodium hydroxide (10 mL) until the color of
iodine persisted. The solid formed was filtered and dried.

Molecules 2006, 11
511
Bis{3-phenyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-on-2-yl}disulfide (13a): Pale
1
yellow cubes, m.p. 277-279 °C (from toluene/chloroform); Yield 73%; IR (cm-1): 1651 (C=O); H-
NMR (CDCl3): 1.79-1.87 (8H, m, 4CH2 at C-6, C-7), 2.74-2.77 (4H, m, 2CH2 at C-5), 2.91-2.95 (4H,
m, 2CH2 at C-8), 7.39-7.42 (4H, m, H-2`, H-6`), 7.55-7.63 (6H, m, H-3`, H-4`, H-5`), 7.39-7.42 (4H,
m, H-2`, H-6`); 13C-NMR: 22.30, 23.01, 25.24, 25.35 (aliphatic ring sp3 carbons), 119.98, 129.40,
130.11, 130.60, 131.87, 133.21, 135.28, 153.09, 161.92 (sp2 carbons); 158.42 (C=O); (C-2); MS: m/z
(%) 626 [M+] (0.4) (C32H26N4O2S4); 314 (100) [M-C16H13N2OS2]; 281 [M-C16H13N2OS2-SH+H] (19).
Bis{3-(4-Chlorophenyl)-7-methyl-5,6,7,8-tetrahydro-3H–pyrido[3`,4`:5,4]thieno[2,3-d]pyrimidin-4-
on-2-yl}disulfide (13b): Yield 65%; m.p. 254-256 °C; IR (cm-1): 1651 (C=O); MS: m/z (%) 363 (91)
[M-C16H13ClN3OS2+H].
General procedure for the synthesis of 14a,b:
A mixture of 1d,e (20 mmol) and triethyl orthoformate (20 mL) was heated under reflux for 4h,
and then evaporated to dryness under reduced pressure. Ethylenediamine (3 g, 50 mmol) was added
dropwise with stirring and the reaction mixture was heated at 100°C for 7 h. The solid product that
separated after cooling was collected by filtration, washed with ethanol, dried and recrystallized from
DMF.
3-(2-Aminoethyl)-4-imino-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine (14a): Fine colorless
needles, m.p. 300-302 °C; Yield 40%; IR (cm-1): 3437-3312 (NH, NH2), 1573, 1564 (2C=N); MS: m/z
(%) 222 [M+] (0.22) (C10H14N4S), 205 [M-NH3] (17), 180 [M-NH3-C2H4+3H] (100).
3-(2-Aminoethyl)-4-imino-3,5,6,7,8,9-hexahydro-4H-cyclohepta[4,5]-thieno[2,3-d]pyrimidine (14b):
Fine colorless needles, m.p. 218-220 °C; Yield 75%; IR (cm-1): 3371-3319 (NH, NH2), 1580, 1555
(2C=N); MS: m/z (%) 262 [M+] (0.4) (C13H18N4S), 245 [M-NH3] (22), 220 [M-NH3-C2H4+3H] (100).
Attempted preparation of 2-amino-4,5-dimethyl-3-(4,5-dihydro-1H-2-imidazolyl)thiophene (15):
Carbon disulfide (1 g, 13 mmol) was added gradually to a suspension of 1d (0.3 g, 2 mmol) and
ethylenediamine (3 g, 50 mmol). The mixture was heated at 100 °C, for 8 h; the solid formed after
cooling was filtered off and washed several times with DMF to give 16 as fine yellow needles, m.p.
217-219 °C; Yield 90%; IR (cm-1): 3245-3167 (NH2, NH), 1207 (C=S); MS: m/z (%) 289 [M+H] (0.2),
272 [M-NH2] (100), 254 [M-H2S-H] (37), 241 [M-H2S-CH3+2H], 221 [M-H2S-CH3-NH2-2H] (34),
162 [M-C6H8NS] (100), 137 [M-C7H9N2S+2H] (35), 102 [M-C7H10N2S2] (40).
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Sample availability: Contact the authors.
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