Convenient and efficient synthesis of some novel fused thieno pyrimidines using gewald's reaction

Article abstract of DOI:10.1080/00397911.2010.515357

Several functionalized thienopyrimidines were synthesized by a facile synthetic method, which includes Gewald's reaction, and were characterized by spectral and analytical data. These functionalized thienopyrimidines were converted to various new chemical

Full text of DOI:10.1080/00397911.2010.515357

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Convenient and Efficient Synthesis of
Some Novel Fused Thieno Pyrimidines
Using Gewald's Reaction
Ramakrishna V. S. Nirogi a , Rama Sastri Kambhampati a , Prabhakar
Kothmirkar a , Sobhanadri Arepalli a , Narasimha Reddy G. Pamuleti a
, Anil K. Shinde a & P. K. Dubey b
a Discovery Research, Medicinal Chemistry, Suven Life Sciences Ltd.,
Hyderabad, Andhra Pradesh, India
b Department of Chemistry, Jawaharlal Nehru Technological
University, Hyderabad, Andhra Pradesh, India
Version of record first published: 29 Jun 2011.
To cite this article: Ramakrishna V. S. Nirogi , Rama Sastri Kambhampati , Prabhakar Kothmirkar ,
Sobhanadri Arepalli , Narasimha Reddy G. Pamuleti , Anil K. Shinde & P. K. Dubey (2011): Convenient
and Efficient Synthesis of Some Novel Fused Thieno Pyrimidines Using Gewald's Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:19, 2835-2851
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Synthetic Communications1, 41: 2835–2851, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515357
CONVENIENT AND EFFICIENT SYNTHESIS OF SOME
NOVEL FUSED THIENO PYRIMIDINES USING
GEWALD’S REACTION
Ramakrishna V. S. Nirogi,1 Rama Sastri Kambhampati,1
Prabhakar Kothmirkar,1 Sobhanadri Arepalli,1
Narasimha Reddy G. Pamuleti,1 Anil K. Shinde,1 and
P. K. Dubey2
1Discovery Research, Medicinal Chemistry, Suven Life Sciences Ltd.,
Hyderabad, Andhra Pradesh, India
2Department of Chemistry, Jawaharlal Nehru Technological University,
Hyderabad, Andhra Pradesh, India
GRAPHICAL ABSTRACT
Abstract Several functionalized thienopyrimidines were synthesized by a facile synthetic
method, which includes Gewald’s reaction, and were characterized by spectral and analyti-
cal data. These functionalized thienopyrimidines were converted to various new chemical
entities of biological importance, such as 2-piperazinymethyl thienopyrimidines (6, 8),
4-dimethylaminoethoxy thienopyrimidines (11), and 3-dimethylaminoethyl thienopyrimi-
dines (12). All the compounds thus synthesized were screened for their invitro biological
activities. Some of the compounds displayed promising serotonin 5-HT6 receptor antagonist
activities.
Keywords Cyclizations; fused thiophenes; Gewald reaction; thieno pyrimidines
Received May 1, 2010.
Address correspondence to Ramakrishna V. S. Nirogi, Discovery Research, Medicinal Chemistry,
Suven Life Sciences Ltd. Serene Chambers, Road No. 5, Avenue 7, Banjara Hills, Hyderabad 500 034,
Andhra Pradesh, India. E-mail: ramakrishna_nirogi@yahoo.co.in
2835

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R. V. S. NIROGI ET AL.
INTRODUCTION
The chemistry of pyrimidine and its derivatives has been studied for more than
a century because of their diverse biological activities.[1–4] They possess antitu-
mor,[5,6] antihypertensive,[7] and anti-inflammatory[8] activities. Thieno pyrimidines,
formed by the fusion of thiophene moiety with pyrimidine ring have been reported
to be chemotherapeutically more active.[9] The derivatives of the thienopyrimidine
system, which are well-known bioisosteres of quinazolines, are of great importance
because of their remarkable biological properties. For example, some 2-alkyl substitu-
ted thienopyrimidinones show significant antifungal and antibacterial activities,[10–13]
whereas others exhibited good anticonvulsant and angiotensin or H1 receptor
antagonistic activities.[14–16] The chemistry of thienopyrimidinones has also received
great attention because their starting materials, 2-amino-3-carboxythiophenes, can
be conveniently synthesized. Though there are many literature methods for the
synthesis of thienopyrimidinones,[17–19] synthesis of various thiophenes and fused
thiophenes by the Gewald method[20–23] followed by their reaction with nitriles to
yield thienopyrimidinones was found to be very attractive. Recently, we reported sub-
stituted 3-piperazinylmethylindole derivatives as highly potent, safe, and orally bio-
available serotonin 5-HT6 receptor ligands. To explore the structure–activity
relationship (SAR) scope and to see the effect of scaffold hopping on the binding
affinities, a series of thienopyrimidine derivatives were designed, synthesized, and
evaluated. The preliminary molecular modeling studies were carried out using CS
ChemOffice software, which showed that the desired pharmacophoric arrangement
required for serotonin 5-HT6 receptor ligands was maintained in the proposed com-
pounds. In vitro studies were carried out by radio-ligand binding assay.
RESULTS AND CONCLUSIONS
Gewald’s reaction of substituted ketones with ethyl cyanoacetate and sulfur in
morpholine and ethanol gave the intermediates 2, which were confirmed by mass and
1H NMR. The reaction of intermediates 2 with chloro acetonitrile or acrylonitrile
and dry hydrogen chloride gas in 1,4-dioxane solvent at 50 ꢀC gave the cyclized
chloroalkyl derivative 3, which was confirmed by the presence of pyrimidine NH
proton at 10 to 12.5 ppm apart from mass. The product, thus obtained, was reacted
with N-alkyl piperazines in the presence of triethylamine in dimethylformamide sol-
vent at 5–10 ꢀC to obtain the intermediate 4. The latter compounds were converted
to the corresponding 4-chloro derivatives 5 by the reaction of intermediates 4 with
phosphorus oxychloride in the presence of triethylamine at reflux temperature.
The formation of intermediate 5 was confirmed by mass and the absence of pyrim-
1
idine NH proton in H NMR. The 4-chloropyrimidine derivatives 5, thus obtained,
were further reacted with various substituted=unsubstituted thiophenols in acetone
in the presence of potassium carbonate to obtain series 1, compounds 6
(Scheme 1), which were confirmed by mass and the presence of aromatic protons
due to the presence of substituted phenyl mercapto group in proton NMR.
Chloro compound 5 was reacted with hydrazine hydrate to give the compound
7. The compound 7 was cyclized with formamide to obtain series 2 compounds 8
1
(Scheme 2), which were confirmed by mass and H NMR. Especially the formation

FUSED THIENO PYRIMIDINES
2837
Scheme 1. Reagents and conditions: (i) morpholine, sulfur, absolute ethanol, ethyl cyanoacetate, 60 ꢀC;
(ii) chloroacetonitrile=acrylonitrile, HCl gas passing, 1,4-dioxane, 50 ꢀC; (iii) DMF, substituted pipera-
zines, TEA, 10 ꢀC to rt; (iv) POCl3, TEA, reflux; (v) K2CO3, substituted thiophenols, acetone, reflux.
R1, R2: ethyl, methyl, or together form a five- or six-membered carbocyclic ring; R3: methyl, ethyl; R4:
hydrogen, methyl, methoxy, chloro, and fluoro; n: 1, 2.
of 8 was confirmed by the appearance of an aromatic proton at a chemical shift value
of 9.38 ppm due to the aromatic CH proton at position 3 on the triazole ring.
The compound 2 was treated with formamide to give the compound 9. The for-
1
mation of the product was confirmed by mass and H NMR. The appearance of a
peak at the chemical shift value of 8.75 ppm due to aromatic CH proton at position
2 of the pyrimidine ring confirmed the formation of the product. The compound 9
was further treated with phosphorous oxychloride to obtain compound 10. The com-
pound 10 was treated with dimethylamino ethanol in the presence of a base to obtain
series 3 compounds 11 (Scheme 3). The formation of the product was once again
confirmed by the mass and proton NMR. The appearance of an additional 10 pro-
tons in the upfield due to the introduction of the dimethylaminoethyl grouping con-
firms the formation of the product 11.
The compound 9 was treated with N,N-dimethylaminoethylchloride to obtain
series 4 compounds 12 (Scheme 4). The formation of the product was confirmed by
infrared (IR), 1H NMR, and mass spectral data. The presence of an absorption peak
at 1672 cmꢁ1 in IR confirms the pyrimidin-4-one grouping. The appearance of an
1
additional 10 protons in the upfield in H NMR due to dimethylaminoethyl group
Scheme 2. Reagents and conditions: (i) hydrazine hydrate, ethanol, 100 ꢀC; (ii) trimethylorthformate,
reflux. R1, R2: ethyl, methyl, together form a five- or six-membered carbocyclic ring, R3: methyl, ethyl;
n: 1, 2.

2838
R. V. S. NIROGI ET AL.
Scheme 3. Reagents and conditions: (i) formamide, 170 ꢀC; (ii) POCl3, TEA, 100 ꢀC; (iii) N,N-
dimethylaminoethanol, Na, toluene, 110 ꢀC. R1, R2: ethyl, methyl, or together form a five- or six-
membered carbocyclic ring; R3: methyl, ethyl; n: 1, 2.
Scheme 4. Reagents and conditions: (i) N,N-dimethylamino ethylchloride hydrochloride, K2CO3, acetone,
60 ꢀC. R1, R2: ethyl, methyl, or together form a five- or six-membered carbocyclic ring.
confirms the introduction of the group at position 3 of the pyrimidine ring. The bind-
ing affinities of thienopyrimidine derivatives were found to be moderate in the micro-
molar range. Further structural modifications are under way to achieve the binding
affinity at the desired levels in the nanomolar range. The major aim of this article
was to report the facile methods leading to the synthesis of novel heterocycles in
good to excellent yields.
EXPERIMENTAL
Melting points were obtained on a B-540 Buchi melting-point apparatus and
are uncorrected. 1H NMR spectra were recorded on a Brucker 400-MHz spec-
trometer with tetramethylsilane (TMS) as the internal standard in deutirated chlor-
ofom or dimethylsulfoxide (DMSO-d6). Element analysis was performed on a Vario
EL (Elementar, Germany) instrument. IR spectra were recorded on a Fourier trans-
form (FT–IR)—(Shimadzu, model IR Prestige-21) spectrophotometer. Chromato-
graphy refers to column chromatography performed using 100- to 200-mesh silica
gel executed under nitrogen pressure (flash chromatography) conditions.
Ethyl 2-Amino-4,5,6,7-tetrahydro Benzothiophene-3-carboxylate (2)
Morpholine (20.4 g, 0.234 mol) was added dropwise to a mixture of cyclohex-
anone (10.0 g, 0.102 mol), ethyl cyanoacetate (11.53 g, 0.102 mol), and sulfur (2.9 g,
0.094 mol) in 30 mL of rectified spirit at ambient temperature in 10 min. The reaction
was exothermic, the mass temperature shot up to 60 ꢀC, and a clear solution was

FUSED THIENO PYRIMIDINES
2839
obtained. It was filtered from suspended solids, and the clear solution was cooled to
0–5 ꢀC, 30 min, and the solids separated. The product was filtered, washed well with
chilled rectified spirit (20 mL), and sucked dry, and finally the cake was dried in an
oven at 50 ꢀC for 2 h to obtain 15.1 g of the title product. Melting point: 110–112 ꢀC,
purity (HPLC) ¼ 99%. Mother liquors were diluted with ice water, and the isolated
second crop was washed with chilled rectified spirit and dried to obtain the product
in an overall yield of 85.0% on sulfur. IR (cmꢁ1): 3414, 3294, 1643, 1601, 1493, 1369,
1
1264, 1163, 1034, 781; mass (m=z): 226.30 (M þ H)þ; % purity (HPLC) ¼ 99.0; H
NMR (ppm): 1.34 (3H, t), 2.30–2.69 (4H, m), 2.70–2.73 (2H, m), 2.79–2.83 (2H,
m), 4.21–4.26 (2H, m), 5.84 (2H, bs).
2-Chloromethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
4-one (3, n ¼ 1)
Ethyl-2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (2.25g, 0.01mol)
and chloroacetonitrile (1.0 g, 0.012 mol) were taken in 1,4-dioxane solvent, heated to
50 ꢀC, and passed with dry hydrogen chloride gas until the starting material was
absent in 3 h. Then the solvent was removed under vacuum. The residual mass was tri-
turated with hexane, and solids separated as fine powder. The product was filtered,
washed with hexane, and air dried to obtain 1.72 g of the compound, the yield being
67.6%. mass (m=z): 255.73 (M þ H)þ; 1H NMR (ppm): 1.80–1.83 (4H, m), 2.89 (2H,
m), 2.92–2.99 (2H, m), 3.89–3.93 (2H, t), 12.12 (1H, bs).
2-[(4-Methylpiperazin-1-yl) methyl]-5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidin-4-one (4, n ¼ 1)
N-Methylpiperazine (120 mg, 1.21 mmol) was added to a mixture of
2-chloromethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (0.248 g,
0.97 mmol), dimethyl formamide (5 mL), and triethylamine (0.5 mL) at 5–10 ꢀC,
and the reaction mass reached ambient temperature under stirring. The reaction
mass was further stirred at room temperature until the reaction was complete in
2 h. Then the mass was quenched in ice water and extracted with ethyl acetate
(3 ꢂ 25 mL). The combined organic layer was washed with brine solution (2 ꢂ 20 mL)
and dried over anhydrous magnesium sulfate. The solvent was removed under
reduced pressure, and the residual mass was purified by column chromatography,
eluent system being 1% triethylamine in ethylacetate, to obtain 0.21 g of the title
product. The yield was 71.3%.
Melting range (ꢀC): 218.5–223.1, IR spectra (cmꢁ1): 2938, 2792, 1655, 1588,
1445, 1288, 1198, 1138, 1010, 826; mass (m=z): 319.3 (M þ H)þ; % purity
1
(HPLC) ¼ 98.36, H NMR (ppm): 1.83–1.89 (4H, m), 2.31 (3H, s), 2.4–2.7 (8H,
m), 2.75–2.78 (2H, m), 2.99–3.02 (2H, m), 3.53 (2H, s), 9.82 (1H, s).
2-Chloroethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-
one (3, n ¼ 2)
Ethyl-2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (18.6 g, 0.083 mol)
and acrylonitrile (7.7 g, 0.145 mol) were dissolved in 1,4-dioxane (100 mL),

2840
R. V. S. NIROGI ET AL.
and dry hydrogen chloride gas was passed at 50 ꢀC slowly until the
reaction was complete in 3 h, the progress of the reaction being monitored by
thin-layer chromatography (TLC). After completion of the reaction, nitrogen
gas was flushed through the mass to remove the excess hydrogen chloride gas,
and then solvent was removed under reduced pressure. The solids that separated
were triturated with hexane and filtered, and the product was washed with
fresh hexane to obtain 19.2 g product. The yield was 86.5%. % Purity
(HPLC) ¼ 95.48; mass (m=z): 269.1 (M þ H)þ; 1H NMR (ppm): 1.83–1.86 (4H,
m), 2.87 (2H, m), 2.96–2.98 (2H, m), 3.11–3.15 (2H, m) 3.91–3.97 (2H, t),
12.05 (1H, bs).
2-[(4-Methylpiperazin-1-yl)ethyl]-5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidin-4-one (4, n ¼ 2)
N-Methylpiperazine (120 mg, 1.21 mmol) was added to a mixture of
2-chloroethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one
(0.248 g,
0.92 mmol), dimethyl formamide (5 mL), and triethylamine (0.5 mL) at 5–10 ꢀC,
and the reaction mass reached ambient temperature under stirring. The reaction
mass was further stirred at room temperature until the reaction was complete in
2 h. The progress of the reaction was followed by TLC. Then the mass was quenched
in ice water and extracted with ethyl acetate (3 ꢂ 25 mL). The combined organic layer
was washed with brine solution (2 ꢂ 20 mL) and dried over anhydrous magnesium
sulfate. The solvent was removed under vacuum, and the residual mass was purified
by column chromatography. IR (cmꢁ1): 2938, 2792, 1665, 1594, 1449, 1291, 1166,
1
1012, 921, 626; mass (m=z): 333.4 (M þ H)þ; % purity (HPLC) ¼ 97.03; H NMR
(ppm): 1.82–1.88 (4H, m), 2.34 (3H, s), 2.5–2.85 (14H, m), 2.98–2.99 (2H, m), 12.5
(1H, bs).
4-Chloro-2-[(4-methylpiperazin-1-yl)methyl]-5,6,7,8-tetrahydrobenzo-
[4,5]thieno[2,3-d]pyrimidine (5)
Triethylamine (3.16 g, 31.28 mmol) was slowly added to a mixture of 2-[(4-
methylpiperazin-1-yl)methyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-
one (1.9 g, 5.97 mmol) and phosphorous oxychloride (10 g, 65.1 mmol), and the mass
was heated at reflux temperature until the reaction was complete in 2 h. The progress
of the reaction was monitored by TLC. After the completion of the reaction, the
mass was quenched in ice water. The pH of the solution was adjusted to 12.0 with
aqueous sodium carbonate solution, and the product was extracted with 3 ꢂ 30 mL
of ethyl acetate. The combined organic layer was washed with brine solution
(2 ꢂ 20 mL) and dried over anhydrous magnesium sulfate. The solvent was removed
under reduced pressure, and the residual mass was purified by column chromato-
graphy, the eluent system being 1% triethylamine in ethylacetate. Weight of the pro-
duct is 1.08 g, purity (HPLC) ¼ 94.0% yield ¼ 53.7%. IR (cmꢁ1): 3401, 2939, 1673,
1
1564, 1484, 1129, 1013, 843, 753, 662; mass (m=z): 337.88 (M þ H)þ; H NMR
(ppm): 1.83–1.94 (4H, m), 2.22 (3H, s), 2.25–2.39 (8H, m), 2.81–2.84 (2H, m),
3.16–3.19 (2H, m), 3.55 (2H, s).

FUSED THIENO PYRIMIDINES
2841
2-[(4-Methylpiperazin-1-yl)methyl]-4-(phenylthio)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6a)
4-Chloro-2-[(4-methylpiperazin-1-yl)methyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno-
[2,3-d]pyrimidine (1.0 g, 2.97mmol), thiophenol (0.393g, 3.57mmol), and anhydrous
potassium carbonate (0.616 g, 4.46mmol) were taken in acetone (10 mL) and refluxed
under a nitrogen blanket until completion of the reaction. The progress of the reaction
was monitored by TLC. After refluxing for a period of 6 h, the solvent was removed
under reduced pressure. The residual mass was suspended in 10 mL water, and the
product was extracted with 3 ꢂ 30 mL of ethyl acetate. The combined organic layer
was washed with brine solution (2ꢂ 10 mL) and dried over anhydrous magnesium sul-
fate. The solvent was removed under reduced pressure, and the residual mass was pur-
ified by column chromatography to obtain 0.77g of the title product, the yield being
63.2%.
Melting range (ꢀC) 100.6–107.5; IR spectra (cm-1): 2932, 2783, 1559, 1492,
1
1294, 1124, 1017, 743; mass (m=z): 411.3 (M þ H)þ; H NMR (ppm): 1.85–1.96
(4H, m), 2.26 (3H, s), 2.28–2.42 (8H, m), 2.84–2.86 (2H, m), 3.14–3.17 (2H, m),
3.6 (2H, s), 7.4–7.44 (3H, m), 7.55–7.58 (2H, m). Anal. calcd. for C22H26N4S2: C,
64.35; H, 6.38; N, 13.64; S, 15.62. Found: C, 64.29; H, 6.34; N, 13.53; S, 15.61%.
5-Ethyl-6-methyl-2-[2-(4-ethylpiperazin-1-yl)methyl]-4-phenylthio-
thieno[2,3-d]pyrimidine (6b)
IR spectra (cmꢁ1): 2968, 2932, 2812, 1644, 1487, 1303, 1143, 835, 748; mass (m=
z): 413.3 (M þ H)þ; 1H NMR (ppm): 1.06–1.09 (3H, t, J ¼ 7.2 Hz), 1.29 – 1.33 (3H, t,
J ¼ 7.48 Hz), 2.35–2.45 (10H, m), 2.5 (3H, s), 3.06–3.12 (2H, q, J ¼ 7.48 Hz), 3.61
(2H, s), 7.41–7.44 (3H, m), 7.58–7.60 (2H, m). Anal. calcd. for C22H28N4S2: C,
64.04; H, 6.84; N, 13.58; S, 15.54. Found: C, 64.12; H, 6.83; N, 13.64; S, 15.58%.
5-Ethyl-6-methyl-2-[2-(4-ethylpiperazin-1-yl)methyl]-4-(4-methoxy
Phenyl Thio)thieno[2,3-d]pyrimidine (6c)
IR spectra (cmꢁ1): 2966, 2933, 2807, 1591, 1486, 1299, 1249, 1143, 826; mass
1
(m=z): 443.5(M þ H)þ; H NMR (ppm): 1.06–1.1 (3H, t, J ¼ 7.28 Hz), 1.28–1.32
(3H, t, J ¼ 7.44 Hz), 2.4–2.49 (8H, m), 2.5 (3H, s), 2.85–2.95 (2H, m), 3.05–3.11
(2H, q), 3.62 (2H, s), 3.86 (3H, s), 6.94–6.97 (2H, m), 7.47–7.51 (2H, m). Anal. calcd.
for C23H30N4OS2: C, 62.41; H, 6.83; N, 12.66; O, 3.61; S, 14.49. Found: C, 62.31; H,
6.85; N, 12.75; O, 3.58; S, 14.45%.
2-[2-(4-Methylpiperazin-1-yl)-ethyl]-4-(4-methoxyphenylthio)-
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6d)
IR spectra (cmꢁ1): 2935, 2837, 1591, 1488, 1416, 1291, 1249, 1130, 834; mass
1
(m=z): 455.2 (M þ H)þ; H NMR (ppm): 1.92–1.93 (2H, b), 2.0 (2H, s), 2.3 (3H,
s), 2.4–2.62 (8H, m), 2.64–2.68 (2H, t, J ¼ 7.36 Hz), 2.84–2.85 (2H, m), 2.9–2.93
(2H, t, J ¼ 7.64 Hz), 3.13–3.15 (2H, m), 3.86 (3H, s), 6.94–6.98 (2H, m), 7.43–7.46

2842
R. V. S. NIROGI ET AL.
(2H, m). Anal. calcd. for C24H30N4OS2: C, 63.40; H, 6.65; N, 12.32; O, 3.52; S, 14.10.
Found: C, 62.99; H, 6.62; N, 11.99; O, 3.50; S, 13.99%.
5-Ethyl-6-methyl-2-[2-(4-methylpiperazin-1-yl)methyl]-4-(4-methoxy
phenyl thio)thieno[2,3-d]pyrimidine (6e)
IR spectra (cmꢁ1): 2964, 2933, 2794, 1591, 1485, 1290, 1248, 1143, 1031, 825;
mass (m=z): 429.1 (M þ H)þ; 1H NMR (ppm): 1.28–1.32 (3H, t, J ¼ 7.48), 2.2 (3H, s),
2.21–2.49 (6H, m), 2.5 (3H, s), 2.91–2.96 (2H, m), 3.05 (2H, q), 3.62 (2H, s), 3.88
(3H, s), 6.94–6.97 (2H, m), 7.47–7.51 (2H m). Anal. calcd. for C22H28N4OS2: C,
61.65; H, 6.58; N, 13.07; O, 3.73; S, 14.96. Found: C, 61.98; H, 6.53; N, 12.99; O,
3.02; S, 14.86%.
2-[2-(4-Ethylpiperazin-1-yl)-ethyl]-4-(4-methoxyphenylthio)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6f)
IR spectra (cmꢁ1): 2935, 2808, 1591, 1488, 1416, 1310, 1248, 1129, 834; mass
(m=z): 469.4 (M þ H)þ; 1H NMR (ppm): 1.06–1.1 (3H, t), 1.83–1.95 (4H, m),
2.38–2.44 (10H, m), 2.61–2.65 (2H, m), 2.84–2.85 (2H, m), 2.9–2.94 (2H, m), 3.13–
3.15 (2H, m), 3.85 (3H, s), 6.93–6.99 (2H, m), 7.43–7.52 (2H, m). Anal. calcd. for
C25H32N4OS2: C, 64.07; H, 6.88; N, 11.95; O, 3.41; S, 13.68. Found: C, 63.95; H,
6.91; N, 11.55; O, 3.52; S, 13.64%.
2-[2-(4-Methylpiperazin-1-yl)-ethyl]-4-phenylthio-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6g)
IR spectra (cmꢁ1): 2937, 2847, 1647, 1489, 1417, 1312, 1130, 835, 753; mass
1
(m=z): 425.1 (M þ H)þ; H NMR (ppm): 1.92–1.93 (4H, m), 2.31 (3H, s), 2.46–
2.48 (6H, m), 2.6–2.63 (2H, m), 2.83–2.86 (2H, m), 2.89–2.93 (2H, m), 3.14–3.16
(4H, m), 7.42–7.44 (3H, m), 7.54–7.56 (2H, m). Anal. calcd. for C23H28N4S2: C,
65.06; H, 6.65; N, 13.19; S, 15.10. Found: C, 64.92; H, 6.71; N, 12.98; S, 14.98%.
5-Ethyl-6-methyl-2-[2-(4-methylpiperazin-1-yl)methyl]-4-phenylthio-
thieno[2,3-d]pyrimidine (6 h)
IR spectra (cmꢁ1): 2965, 2932, 2798, 1648, 1486, 1143, 1012, 835, 748; mass
1
(m=z): 399.2 (M þ H)þ; H NMR (ppm): 1.29–1.33 (3H, t, J ¼ 7.52 Hz), 2.26 (3H,
s), 2.3–2.5 (8H, b), 2.5 (3H, s), 3.06–3.11 (2H, q, J ¼ 7.48 Hz), 3.6 (2H, s), 7.42–
7.44 (3H, m), 7.57–7.6 (2H, m). Anal. calcd. for C21H26N4S2: C, 63.28; H, 6.57;
N, 14.06; S, 16.09. Found: C, 62.98; H, 6.52; N, 13.94; S, 15.96%.
2-[2-(4-Ethylpiperazin-1-yl)-ethyl]-4-phenylthio-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6i)
IR spectra (cmꢁ1): 2936, 2813, 1488, 1311, 1130, 835, 750; mass (m=z): 439.3
(M þ H)þ; 1H NMR (ppm): 1.07–1.11 (3H, t, J ¼ 7.64 Hz), 1.92–1.98 (4H, m),
2.43–2.48 (8H, m), 2.59–2.63 (2H, m), 2.83–2.85 (2H, m), 2.90–2.94 (2H, m),

FUSED THIENO PYRIMIDINES
2843
3.0–3.1 (2H, m), 3.14–3.16 (2H, m), 7.40–7.44 (3H, m), 7.54–7.56 (2H, m). Anal.
calcd. for C24H30N4S2: C, 65.72; H, 6.89; N, 12.77 S, 14.62. Found: C, 65.01; H,
6.91; N, 12.61; S, 14.54%.
4-(4-Chlorophenylthio)-6-(4-ethylpiperazin-1-ylmethyl)-2,3-dihydro-
1H-8-thia-5,7-diazacyclopenta[a]indene (6j)
IR spectra (cmꢁ1): 2942, 2809, 1489, 1477, 1443, 1300, 1092, 821; mass (m=z):
445.4 (M þ H)þ; 1H NMR (ppm): 1.09–1.13 (3H, t, J ¼ 7.52 Hz), 2.46–2.58 (12H, m),
3.02–3.06 (2H, m), 3.18–3.21 (2H, m), 3.69 (2H, s), 7.39–7.42 (2H, m), 7.51–7.54 (2H,
m). Anal. calcd. for C22H25ClN4S2: C, 59.37; H, 5.66; Cl, 7.97; N, 12.59; S, 14.41.
Found: C, 58.96; H, 5.62; Cl, 7.91; N, 12.63; S, 14.42%.
4-(4-Chlorophenylthio)-6-(4-methylpiperazin-1-ylmethyl)-2,3-
dihydro-1H-8-thia-5,7-diazacyclopenta[a]indene (6k)
Melting range (ꢀC) 126.9–129.4; IR spectra (cmꢁ1): 2950, 2808, 1484, 1296,
1
1148, 1011, 818; mass (m=z): 431.4 (M þ H)þ; H NMR (ppm): 2.41 (3H, s), 2.5–
2.7 (10H, m), 3.03–3.06 (2H, m), 3.18–3.22 (2H, m), 3.7 (2H, s), 7.4–7.43 (2H, m),
7.5–7.53 (2H, m). Anal. calcd. for C21H23ClN4S2: C, 58.52; H, 5.38; Cl, 8.23; N,
13.00; S, 14.88. Found: C, 57.96; H, 5.41; N, 12.99; S, 14.83%.
4-(Phenylthio)-6-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-1H-8-
thia-5,7-diazacyclopenta[a]indene (6 l)
Melting range (ꢀC) 105.4–118.1; IR spectra (cmꢁ1): 2950, 2808, 1484, 1296,
1
1148, 1011, 818; mass (m=z): 397.2 (M þ H)þ; H NMR (ppm): 2.31 (3H, s), 2.48–
2.57 (10H, m), 3.02–3.06 (2H, m), 3.2–3.23 (2H, m), 3.66 (2H, s), 7.39–7.45 (3H,
m), 7.56–7.61 (2H, m). Anal. calcd. for C21H24N4S2: C, 63.60; H, 6.10; N, 14.13;
S, 16.17. Found: C, 63.96; H, 5.99; N, 13.86; S, 15.98%.
2-[(4-Ethylpiperazin-1-yl) Methyl]-4-(4-methoxyphenylthio)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6 m)
IR spectra (cmꢁ1): 2935, 2800, 1590, 1490, 1289, 1245, 1179, 822; mass (m=z):
1
455.2 (M þ H)þ; H NMR (ppm): 1.1–1.14 (3H, t, j ¼ 7.64 Hz), 1.92–1.93 (4H, m),
2.5–2.62 (10H, m), 2.84–2.86 (2H, m), 3.14–3.16 (2H, m), 3.63 (2H, s), 3.86 (3H,
s), 6.94–6.97 (2H, m), 7.46–7.48 (2H, m). Anal. calcd. for C24H30N4OS2: C, 63.40;
H, 6.65; N, 12.32; O, 3.52; S, 14.10. Found: C, 62.98; H, 6.68; N, 12.66; O, 3.48;
S, 13.96%.
4-(4-Methoxyphenylthio)-6-(4-methylpiperazin-1-ylmethyl)-2,3-
dihydro-1H-8-thia-5,7-diazacyclopenta[a]indene (6n)
Melting range (ꢀC) 117.5–128.8; IR spectra (cmꢁ1): 2932, 2785, 1589, 1489,
1
1246, 1179, 1019, 822; mass (m=z): 427.2 (M þ H)þ; H NMR (ppm): 2.37 (3H, s),
2.5–2.58 (10H, m), 3.02–3.06 (2H, m), 3.19–3.23 (2H, m), 3.67 (2H, s), 3.87 (3H,

2844
R. V. S. NIROGI ET AL.
s), 6.94–6.97 (2H, m), 7.47–7.5 (2H, m). Anal. calcd. for C22H26N4OS2: C, 61.94; H,
6.14; N, 13.13; O, 3.75; S, 15.03. Found: C, 62.01; H, 6.09; N, 12.99; O, 3.72; S, 15.08%.
2-[(4-Methylpiperazin-1-yl)methyl]-4-(4-methoxyphenylthio)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6o)
Melting range (ꢀC) 85.4–92.1, IR spectra (cmꢁ1): 2931, 2783, 1591, 1488, 1294,
1252, 1128, 1016, 828; mass (m=z): 441.3 (M þ H)þ; 1H NMR (ppm): 1.21–1.25 (4H,
m), 2.4 (3H, s), 2.53 (8H, m), 2.84–2.86 (2H, m), 3.14–3.16 (2H, m), 3.63 (2H, s), 3.86
(3H, s), 6.94–6.98 (2H, m), 7.45–7.48 (2H, m). Anal. calcd. for C23H28N4OS2: C,
62.70; H, 6.41; N, 12.72; O, 3.63; S, 14.55. Found: C, 62.11; H, 6.44; N, 12.74; O,
3.52; S, 14.51%.
2-[(4-Ethylpiperazin-1-yl)methyl]-4-phenylthio-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6p)
IR spectra (cmꢁ1): 2934, 2808, 1488, 1300, 1162, 1130, 1023, 834, 748; mass
1
(m=z): 424.63 (M þ H)þ; H NMR (ppm): 1.05–1.09 (3H, t, J ¼ 7.6 Hz), 1.92–1.96
(4H, m), 2.38–2.44 (10H, m), 2.85–2.86 (2H, m), 3.15–3.17 (2H, m), 3.61 (2H, s),
7.4–7.44 (3H, m), 7.56–7.58 (2H, m). Anal. calcd. for C23H28N4S2: C, 65.06; H,
6.65; N, 13.19; S, 15.10. Found: C, 64.95; H, 6.66; N, 12.99; S, 14.98%.
4-(4-Phenylthio)-6-(4-ethylpiperazin-1-ylmethyl)-2,3-dihydro-1H-8-
thia-5,7-diazacyclopenta[a]indene (6q)
IR spectra (cmꢁ1): 2931, 2808, 1529, 1483, 1300, 1148, 1023, 784; mass (m=z):
411.2 (M þ H)þ; 1H NMR (ppm): 1.07–1.11 (3H, t, J ¼ 7.6 Hz), 2.44–2.57 (12H, m),
3.02–3.06 (2H, m), 3.2–3.23 (2H, m), 3.67 (2H, s), 7.42–7.44 (3H, m), 7.58–7.6 (2H,
m). Anal. calcd. for C22H26N4S2: C, 64.35; H, 6.38; N, 13.64; S, 15.62. Found: C,
63.98; H, 6.42; N, 13.61; S, 15.51%.
4-(4-Methoxyphenylthio)-6-(4-ethylpiperazin-1-ylmethyl)-2,3-
dihydro-1H-8-thia-5,7-diazacyclopenta[a]indene (6r)
Melting range (ꢀC) 93.3–105.3, IR spectra (cmꢁ1): 2930, 2808, 1589, 1490,
1
1298, 1248, 1019, 830; mass (m=z): 441.3 (M þ H)þ; H NMR (ppm): 1.12–1.16
(3H, t, J ¼ 7.6 Hz), 2.44–2.56 (12H, m), 3.02–3.05 (2H, t, J ¼ 7.6 Hz), 3.19–3.23
(2H, t, J ¼ 7.52 Hz), 3.67 (2H, s), 3.87 (3H, s), 6.94–6.98 (2H, m), 7.48–7.51 (2H,
m). Anal. calcd. for C23H28N4OS2: C, 62.70; H, 6.41; N, 12.72; O, 3.63; S, 14.55.
Found: C, 62.81; H, 6.43; N, 12.82; O, 3.51; S, 14.62%.
5,6-Dimethyl-2-[(4-methylpiperazin-1-yl)methyl]-4-phenylthio
Thieno[2,3-d]pyrimidine (6s)
IR spectra (cmꢁ1): 2932, 2793, 1560, 1488, 1289, 1145, 1013, 835, 746, 688;
1
mass (m=z): 384.57 (M þ H)þ; H NMR (ppm): 2.25 (3H, s), 2.3–2.43 (8H, m),
2.47 (3H, s), 2.62 (3H, s), 3.59 (2H, s), 7.41–7.44 (3H, m), 7.56–7.58 (2H, m). Anal.

FUSED THIENO PYRIMIDINES
2845
calcd. for C20H24N4S2: C, 62.47; H, 6.29; N, 14.57; S, 16.68. Found: C, 62.31; H,
6.28; N, 13.99; S, 16.72%.
4-(4-Fluorophenylthio)-6-(4-ethylpiperazin-1-ylmethyl)-2,3-dihydro-
1h-8-thia-5,7-diazacyclopenta[a]indene (6t)
Melting range (ꢀC) 99.3–102.4, IR spectra (cmꢁ1): 2937, 2810, 1587, 1483,
1
1300, 1148, 837; mass (m=z): 429.3 (M þ H)þ; H NMR (ppm): 1.14–1.17 (3H, t,
j ¼ 7.64 Hz), 2.51–2.68 (12H, m), 3.03–3.06 (2H, t, j ¼ 7.6 Hz), 3.19–3.23 (2H, t,
j ¼ 7.6 Hz), 3.68 (2H, s), 7.11–7.17 (2H, m), 7.54–7.59 (2H, m). Anal. calcd. for
C22H25FN4S2: C, 61.65; H, 5.88; F, 4.43; N, 13.07; S, 14.96. Found: C, 60.95; H,
5.91; F, 4.38; N, 12.98; S, 14.84%.
4-(4-Fluorophenylthio)-6-(4-methylpiperazin-1-ylmethyl)-2,3-
dihydro-1h-8-thia-5,7-diazacyclopenta[a]indene (6u)
Melting range (ꢀC) 126.2–127.2, IR spectra (cmꢁ1): 3048, 2924, 1609, 1486, 1302,
1148, 838;,mass (m=z): 415.2 (M þ H)þ; 1H NMR (ppm): 2.51–2.57 (2H, m), 2.58 (3H,
s), 2.66–3.0 (8H, m), 3.02–3.08 (2H, m), 3.18–3.24 (2H, m), 3.71 (2H, s), 7.13–7.19 (2H,
m), 7.53–7.58 (2H, m). Anal. calcd. for C21H23FN4S2: C, 60.84; H, 5.59; F, 4.58; N,
13.51; S, 15.47. Found: C, 60.73; H, 5.61; F, 4.56; N, 13.61; S, 15.50%.
2-[(4-Methylpiperazin-1-yl)methyl]-4-(4-fluorophenylthio)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6v)
Melting range (ꢀC) 98.2–110.2, IR spectra (cmꢁ1): 2927, 2789, 1588, 1488,
1
1221, 1016, 817; mass (m=z): 429.3 (M þ H)þ; H NMR (ppm): 1.88–1.98 (4H, m),
2.27 (3H, s), 2.3–2.5 (8H, m), 2.84–2.86 (2H, m), 3.13–3.15 (2H, m), 3.61 (2H, s),
7.1–7.14 (2H, m), 7.52–7.56 (2H, m). Anal. calcd. for C22H25FN4S2: C, 61.65; H,
5.88; F, 4.43: N, 13.07; S, 14.96. Found: C, 61.13; H, 5.86; F, 4.47; N, 13.68; S,
14.90%.
2-[(4-Methylpiperazin-1-yl)methyl]-4-(4-chlorophenylthio)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (6w)
Melting range (ꢀC) 106.5–110.7, IR spectra (cmꢁ1): 2931, 2792, 1489, 1475,
1
1293, 1164, 1012, 844; mass (m=z): 445.4 (M þ H)þ; H NMR (ppm): 1.88–1.96
(4H, m), 2.28 (3H, s), 2.3–2.55 (8H, m), 2.84–2.86 (2H, m), 3.12–3.14 (2H, m),
3.63 (2H, s), 7.39–7.41 (2H, m), 7.48–7.51 (2H, m). Anal. calcd. for C22H25ClN4S2:
C, 59.37; H, 5.66; Cl, 7.97; N, 12.59; S, 14.41. Found: C, 59.13; H, 5.68; Cl, 7.17; N,
12.68; S, 14.14%.
4-Hydrazino-2-[(4-methylpiperazin-1-yl)methyl]-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (7)
4-Chloro-2-[(4-methylpiperazin-1-yl)methyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno-
[2,3-d]pyrimidine (600 mg, 1.78 mmol) and hydrazine hydrate (107.2 mg, 2.14 mmol)

2846
R. V. S. NIROGI ET AL.
were taken in absolute ethanol (30 mL) and heated at 100 ꢀC for 3 h under a nitrogen
blanket. The progress of the reaction was monitored by TLC. After completion of
the reaction, solvent ethanol was removed under reduced pressure. The residual
Mass was diluted with water, and the pH of the resulting solution was adjusted to
10.0 using aqueous ammonia solution. The product was extracted with 3 ꢂ 50 mL
of chloroform. The combined organic layer was washed with brine solution
(2 ꢂ 30 mL) and dried over anhydrous magnesium sulfate. The solvent was removed
under vacuum to obtain 320 mg of the product. It was used as such without further
purification in the next step for the preparation of triazole derivative. IR (cmꢁ1):
3273, 2918, 1625, 1550, 1449, 1182, 1161, 942, 882, 756; mass (m=z): 333.1 (M þ H)þ;
1
; H NMR (ppm): 1.94–1.97 (4H, m), 2.34 (3H, s), 2.44–2.59 (8H, m), 2.9 (2H, m),
3.26–3.27 (2H, m), 4.04 (2H, s), 4.54 (3H, bs).
2-[(4-Methylpiperazin-1-yl)methyl]-6,7,8,9-tetrahydrobenzo[4,5]-
thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (8a)
4-Hydrazino-2-[(4-methylpiperazin-1-yl)methyl]-5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidine (0.32 g, 0.96 mmol) and trimethyl orthoformate
(3.0 mL) were refluxed under a nitrogen atmosphere. The reaction was complete
in 5 h, and the progress of the reaction was monitored by TLC. The excess
trimethyl orthoformate was disuntiled off under reduced pressure, and the
residual Mass was purified by column chromatography to obtain 60 mg of the title
product.
IR spectra (cmꢁ1): 2938, 2791, 1613, 1456, 1291, 1165, 1012, 821; mass (m=z):
343.1 (M þ H)þ; 1H NMR (ppm): 1.96–1.99 (4H, m), 2.32 (3H, s), 2.48–2.63 (8H, m),
2.9 (2H, m), 3.25–3.26 (2H, m), 4.01 (2H, s), 9.38 (1H, s). Anal. calcd. for
C17H22N6S: C, 59.62; H, 6.48; N, 24.54; S, 9.36. Found: C, 59.02; H, 6.49; N,
24.24; S, 9.41%.
6,7-Dimethyl-2-[(4-methylpiperazin-1-yl)methyl]thieno[3,2-e]-
[1,2,4]triazolo [4,3-c]pyrimidine (8b)
IR spectra (cmꢁ1): 2925, 1610, 1457, 1290, 1162, 1010, 821; mass (m=z): 317.2
1
(M þ H)þ; H NMR (ppm): 2.3 (3H, s), 2.55 (3H, s), 2.62 (8H, m), 2.75 (3H, s), 4.0
(2H, s), 9.4 (1H, s). Anal. calcd. for C15H20N6S: C, 56.94; H, 6.37; N, 26.56; S, 10.13.
Found: C, 56.74; H, 6.39; N, 26.66; S, 10.01%.
2-[(4-Methylpiperazin-1-yl)methyl]cyclopentathieno[3,2-e]-
[1,2,4]triazolo[4,3-c]pyrimidine (8c)
Melting range (ꢀC) 178.5–183.4; IR spectra (cmꢁ1): 2938, 2792, 1616, 1456,
1
1287, 1166, 1016, 987, 819, 641; Mass (m=z): 329.3 (M þ H)þ; H NMR (ppm):
2.3 (3H, s), 2.47–2.63 (10H, m), 3.1–3.14 (2H, m), 3.28–3.32 (2H, m), 4.01 (2H, s),
9.39 (1H, s). Anal. calcd. for C16H20N6S: C, 58.51; H, 6.14; N, 25.59; S, 9.76. Found:
C, 58.01; H, 6.09; N, 25.49; S, 9.82%.

FUSED THIENO PYRIMIDINES
2847
6,7-Dimethyl-2-[(4-ethylpiperazin-1-yl)methyl]thieno[3,2-e]-
[1,2,4]triazolo[4,3-c]pyrimidine (8d)
IR spectra (cmꢁ1): 2924, 2808, 1611, 1452, 1303, 1161, 1015, 806; mass (m=z):
1
331.3 (M þ H)þ; H NMR (ppm): 1.07–1.11 (3H, t, J ¼ 7.6 Hz), 2.43–2.49 (2H, q,
J ¼ 7.6 Hz), 2.52 (3H, s), 2.6–2.7 (8H, m), 2.75 (3H, s), 4.0 (2H, s), 9.4 (1H, s). Anal.
calcd. for C16H22N6S: C, 58.15; H, 6.71; N, 25.43; S, 9.70. Found: C, 57.85; H, 6.76;
N, 25.33; S, 9.72%.
2-[(4-Ethylpiperazin-1-yl)methyl]-6,7,8,9-tetrahydrobenzo[4,5]thieno
[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (8e)
IR spectra (cmꢁ1): 2938, 2809, 1612, 1470, 1303, 1168, 1083; mass (m=z): 357.1
1
(M þ H)þ; H NMR (ppm): 1.07–1.11 (3H, t, J ¼ 7.68 Hz), 1.96–1.99 (2H, m), 2.03
(2H, m), 2.4–2.47 (2H, q, J ¼ 7.64 Hz), 2.49–2.63 (8H, m), 2.9–2.95 (2H, m), 3.25–
3.3 (2H, m), 4.01 (2H, s), 9.4 (1H, s). Anal. calcd. for C18H24N6S: C, 60.65; H,
6.79; N, 23.57; S, 8.99. Found: C, 60.05; H, 6.82; N, 23.59; S, 8.89%.
2-[(4-Ethylpiperazin-1-yl)methyl]cyclopentathieno[3,2-e][1,2,4]-
triazolo[4,3-c]pyrimidine (8f)
Melting range (ꢀC) 124.6–127.8; IR spectra (cmꢁ1): 2946, 2813, 1617, 1566,
1
1475, 1452, 1304, 1165, 1016, 641; mass (m=z): 343.2 (M þ H)þ; H NMR (ppm):
1.11–1.13 (3H, t, J ¼ 7.68 Hz), 2.48–2.53 (2H, q, J ¼ 7.64 Hz), 2.58–2.63 (2H, quin,
J ¼ 7.6 Hz), 2.67 (6H, s), 3.1–3.14 (4H, m), 3.27–3.31 (2H, m), 4.02 (2H, s), 9.38
(1H, s). Anal. calcd. for C17H22N6S: C, 59.62; H, 6.48; N, 24.54; S, 9.36. Found:
C, 59.39; H, 6.51; N, 24.61; S, 9.29%.
2-[(4-Ethylpiperazin-1-yl)ethyl]-6,7,8,9-tetrahydrobenzo[4,5]thieno-
[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (8g)
IR spectra (cmꢁ1): 2920, 284909, 1616, 1453, 1274, 1163, 1006; mass (m=z):
1
371.3 (M þ H)þ; H NMR (ppm): 1.08–1.12 (3H, t, J ¼ 7.2 Hz), 1.96–1.99 (4H, m),
2.42–2.48 (2H, q, J ¼ 7.2 Hz), 2.2–2.7 (8H, m), 2.9–2.94 (2H, m), 3.01–3.05 (2H, t,
J ¼ 7.12 Hz), 3.2–3.25 (2H, m), 3.32–3.35 (2H, t, J ¼ 7.12 Hz), 8.93 (1H, s). Anal.
calcd. for C19H26N6S: C, 61.59; H, 7.07; N, 22.68; S, 8.65. Found: C, 61.62; H,
7.11; N, 22.53; S, 8.58%.
5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (9)
Ethyl-2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (10.32 g, 45.86 mmol)
was taken in formamide (44 mL) and heated to 170 ꢀC Mass temperature under a
nitrogen atmosphere. The heating was continued until the reaction was complete,
and the progress of the reaction was monitored by TLC. After 8 h, the reaction Mass
was cooled to 10 ꢀC, and solids were thrown out. The solids were filtered, and the cake
was washed with 50 mL of hexane. The product was sucked dry and finally dried in an
oven at 50 ꢀC, the yield being quantitative. IR spectra (cmꢁ1): 3156, 3007, 2939, 2923,

2848
R. V. S. NIROGI ET AL.
1659, 1590, 1372, 990, 913, 580; mass (m=z): 207.1 (M þ H)þ; % purity
(HPLC) ¼ 98.85. The material was utilized in the next step without any further puri-
fication. IR (cmꢁ1): 2939, 2857, 1659, 1590, 1372, 1170, 990, 913, 580; mass (m=z):
207.0 (M þ H)þ; 1H NMR (ppm): 1.86–1.88 (4H, m), 2.91–2.93 (4H, m), 8.75 (1H, s).
4-Chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (10)
5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (10 g, 48.54 mmol)
was taken in 40 mL of phosphorousoxychloride, the mass was cooled to 15–20 ꢀC,
and triethyl amine (32 mL) was added dropwise, maintaining the temperature below
20 ꢀC, for 15 min. Then, the reaction Mass was slowly heated to 100 ꢀC and main-
tained there for 2 h. The progress of the reaction was monitored by TLC. After com-
pletion of the reaction, the reaction mass was quenched in 250 mL of ice water, and
the product was extracted with 3 ꢂ 50 mL of ethyl acetate. The combined organic
layer was washed with brine solution (2 ꢂ 30 mL) and dried over anhydrous magnes-
ium sulfate. The solvent was removed under reduced pressure, and the residual mass
(10.5 g, yield ¼ 96.3%) was used for the next step without further purification. IR
(cmꢁ1): 2938, 1647, 1596, 1491, 1295, 1153, 1027, 781, 640; mass (m=z): 224.9
1
(M þ H)þ; H NMR (ppm): 1.84–1.89 (4H, m), 2.93–2.98 (4H, m), 8.72 (1H, s).
4-Dimethylaminoethoxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-
d]pyrimidine (11a)
Sodium (94.6 mg, 4.11 mmol) was taken in 50 mL of toluene, and 2-dimethyla-
minoethanol (284 mg, 4.11 mmol) was added dropwise at ambient temperature.
Then, the mass was heated to reflux and maintained under reflux for 1 h. To this
mass was added the prepared 4-chloro derivative 10 (0.6 g dissolved in 5 mL toluene)
at 90 ꢀC. The mass was once again heated to 110 ꢀC and maintained at reflux until
the completion of the reaction. The progress of the reaction was monitored by
TLC. Then the reaction mass was cooled to 25 ꢀC, and toluene was removed under
reduced pressure. The residual mass was dissolved in chloroform and filtered from
inorganic matter. The filtrate was concentrated under reduced pressure, and the tech-
nical product, thus obtained, was purified by column chromatography to get 300 mg
of the pure product, the yield being 40%.
IR spectra (cmꢁ1): 2937, 2858, 1562, 1508, 1448, 1316, 1035; mass (m=z): 278.2
(M þ H)þ; 1H NMR (ppm): 1.85–1.91 (4H, m), 2.42 (6H, s), 2.81–2.84 (2H, m), 2.9–
2.96 (4H, m), 4.65–4.68 (2H, m), 8.76 (1H, s). Anal. calcd. for C14H19N3OS: C,
60.62; H, 6.90; N, 15.15; O, 5.77; S, 11.56. Found: C, 60.92; H, 6.89; N, 15.20; O,
5.69; S, 11.62%.
[2-(2,3-Dihydro-1H-8-thiA-5,7-diazacyclopenta[a]inden-4-yloxy)-
ethyl]dimethylamine(11b)
Melting range: 170–180 ꢀC, IR spectra (cmꢁ1): 2958, 2680, 1562, 1578, 1452,
1
1335, 1049, 1001; mass (m=z): 264.3 (M þ H)þ; H NMR (ppm): 2.52–2.58 (2H,
m), 3.03–3.11 (10H, m), 3.7–3.73 (2H, s), 4.93–4.95 (2H, m), 8.54 (1H, s). Anal.

FUSED THIENO PYRIMIDINES
2849
calcd. for C13H17N3OS: C, 59.29; H, 6.51; N, 15.96; O, 6.08; S, 12.18. Found: C,
58.99; H, 6.53; N, 15.89; O, 6.12; S, 12.22%.
5,6-Dimethyl-4-dimethylaminoethoxythieno[2,3-d]pyrimidine (11c)
IR spectra (cmꢁ1): 2924, 1561, 1509, 1449, 1327, 1159, 1035, 788; mass (m=z):
252.3 (M þ H)þ; 1H NMR (ppm): 2.43 (3H, s), 2.44 (9H, s), 2.95–2.98 (2H, m), 4.68–
4.72 (2H, m), 8.51 (1H, s). Anal. calcd. for C12H17N3OS: C, 57.34; H, 6.82; N, 16.72;
O, 6.37; S, 12.76. Found: C, 57.44; H, 6.85; N, 16.81; O, 6.41; S, 12.81%.
5-Ethyl-6-methyl-4-dimethylaminoethoxythieno[2,3-d]pyrimidine
(11d)
IR spectra (cmꢁ1): 2925, 1557, 1508, 1441, 1326, 1158, 1034, 756; mass (m=z):
1
266.0 (M þ H)þ; H NMR (ppm): 1.03–1.07 (3H, t, J ¼ 7.0 Hz), 2.51 (2H, t), 2.86–
2.92 (8H, m), 3.36 (3H, bs), 4.87–4.9 (2H, t, J ¼ 5.04 Hz), 8.6 (1H, s). Anal. calcd.
for C13H19N3OS: C, 58.84; H, 7.22; N, 15.83; O, 6.03; S, 12.08. Found: C, 58.64;
H, 7.24; N, 15.91; O, 6.06; S, 12.12%.
5-(2-Dimethylaminoethyl)-1,2,3,5-tetrahydro-8-thia-5,7-
diazacyclopenta[a]inden-4-one (12a)
The raw material, 1,2,3,5-tetrahydro-8-thia-5,7-diazacyclopenta[a]inden-4-one
(392 mg, 2.02 mmol), was taken in acetone (10 mL). To this reaction Mass, 2-
dimethylaminoethylchloride hydrochloride, (319.1 mg, 2.215 mmol) and potassium
carbonate (562.6 mg, 4.07 mmol) were added, and the resulting mass was heated to
reflux. It was maintained under reflux (55 ꢀC to 60 ꢀC) until completion of the reac-
tion. The progress of the reaction was monitored by TLC. The mass was cooled to
25 ꢀC, the solids were filtered and washed with acetone (10 mL), and the filtrate was
concentrated under reduced pressure. The residual Mass was purified by column
chromatography to obtain 288 mg of the title product, the yield being 53.68%. Melt-
ing range of the hydrochloride salt was 210–217 ꢀC.
IR spectra (cmꢁ1): 2951, 2855, 1672, 1570, 1443, 1391, 1141, 974; mass (m=z):
1
264.0 (M þ H)þ; H NMR (ppm): 2.3 (6H, s), 2.44–2.48 (2H, m, J ¼ 7.28 Hz), 2.65–
2.68 (2H, t, J ¼ 6.32 Hz), 2.94–2.97 (2H, t, J ¼ 7.24 Hz), 3.07–3.09 (2H, t, J ¼ 7.2 Hz),
4.07–4.1 (2H, t, J ¼ 6.28 Hz), 7.93 (1H, s). Anal. calcd. for C13H17N3OS: C, 59.29; H,
6.51; N, 15.96; O, 6.08; S, 12.18. Found: C, 59.36; H, 6.55; N, 15.95; O, 6.04; S,
12.15%.
5-Ethyl-6-methyl-3-dimethylaminoethyl-4-thieno[2,3-d]pyrimidin-4-
one (12b)
IR spectra (cmꢁ1): 2968, 2768, 1658, 1571, 1458, 1285, 1141, 1037, 790;
1
mass (m=z): 266.0 (M þ H)þ; H NMR (ppm): 1.15–1.19 (3H, t, J ¼ 7.44 Hz), 2.28
(6H, s), 2.41 (3H, s), 2.61–2.64 (2H, t, J ¼ 6.24 Hz), 2.91–2.96 (2H, q, J ¼ 7.44 Hz),
4.04–4.07 (2H, t, J ¼ 6.2 Hz), 7.94 (1H, s). Anal. calcd. for C13H19N3OS: C,

2850
R. V. S. NIROGI ET AL.
58.84; H, 7.22; N, 15.83; O, 6.03; S, 12.08. Found: C, 58.44; H, 7.18; N, 15.75; O,
6.05; S, 12.02%.
3-Dimethylaminoethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-one (12c)
IR spectra (cmꢁ1): 2936, 1670, 1571, 1385, 1137, 775; mass (m=z): 278.2
(M þ H)þ; 1H NMR (ppm): 1.83–1.88 (4H, m), 2.28 (6H, s), 2.6–2.63 (2H, t,
J ¼ 6.2 Hz), 2.76–2.79 (2H, m), 3.01–3.04 (2H, m), 4.02–4.05 (2H, t, J ¼ 6.2 Hz),
7.91 (1H, s). Anal. calcd. for C14H19N3OS: C, 60.62; H, 6.90; N, 15.15; O, 5.77; S,
11.56. Found: C, 60.42; H, 6.94; N, 15.22; O, 5.79; S, 11.53%.
ACKNOWLEDGMENT
The support received from the Discovery Analytical Department and
Venkateswarlu Jasti, CEO, Suven Life Sciences Ltd., Hyderabad, is gratefully
acknowledged.
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