May 2007
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needles; mp 154—156 °C; IR (KBr) cmꢀ1: 3393 (–OH), 3200 (–NH), 2923
(–CH2), 1655 (–CꢂC–), 1066 (–C–N). 1H-NMR (CDCl3) d: 1.81—1.95
(4H, m), 2.23—2.30 (2H, pentet, Jꢂ6.1 Hz), 2.72—2.84 (2H, t, Jꢂ5.7 Hz),
2.92—2.94 (2H, t, Jꢂ5.7 Hz), 3.64—3.72 (2H, t, Jꢂ6.2 Hz), 3.88—3.92
(2H, t, Jꢂ6.2 Hz), 5.47 (1H, s), 7.41—7.50 (3H, m), 8.44—8.52 (2H, d,
Jꢂ6.3 Hz). MS m/z: 340 (Mꢃꢃ1). Anal. Calcd for C19H21N3SO: C, 66.95;
H, 5.85; N, 12.05. Found: C, 67.25; H, 6.19; N, 12.38.
with TMS as internal standard. MS spectra (EI-MS, 70 eV) were recorded
on Autospec spectrometer. Elemental analyses were performed on Carlo
Erba 1108 elemental analyzer (Heraeus, Hanau, Germany) and were within
ꢁ0.4% of theoretical values. All the chemicals used were of analytical
grade.
2-Substituted-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4[3H]-
ones (2a—f). General Procedure 2-Amino-3-carbethoxy-4,5,6,7-tetrahy-
drobenzo[b]thiophene 1 (8.3 mmol), potassium tert-butoxide (0.089 g, 0.8
mmol) and various nitriles (16 mmol) were taken in a 5 ml microwave reac-
tion vial equipped with a magnetic stir bar. The reaction mixture was irradi-
ated in the microwave oven at 120 °C for 45—150 s. To the reaction mixture
at room temperature, crushed ice was added and neutralized using dilute hy-
drochloric acid. The precipitate obtained was filtered, dried and recrystalized
from ethylacetate to give the target compounds in 50—80% yields.
2-(p-Chlorobenzyl)-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-
4[3H]-one (2e) Reaction time: 150 s. Yield 75%; colorless needles; mp
286—288 °C; IR (KBr) cmꢀ1: 1654 (–CꢂO), 3417 (–NH), 2921 (–CH2),
3008 (Ar-H), 1046 (–C–N). 1H-NMR (CDCl3) d: 1.75—1.95 (4H, m),
2.65—2.95(4H, m), 4.12 (2H, s), 8.34—9.15 (4H, m), 11.4 (1H, br-s). MS
m/z: 331.5 (Mꢃꢃ1). Anal. Calcd for C17H15N2SOCl: C, 61.72; H, 4.53; N,
8.47. Found: C, 61.35; H, 4.45; N, 8.10.
2-(p-Chlorobenzyl)l-4-[(3-hydroxy)propyl]amino-5,6,7,8-tetrahy-
drobenzo[b]thieno[2,3-d]pyrimidine (4e) Reaction time: 15 s. Yield 88%;
colorless needles; mp 230—232 °C; IR (KBr) cmꢀ1: 3400 (–OH), 3355
1
(–NH), 2924 (–CH2), 3016 (Ar-H), 1048 (–C–N), 1650 (–CꢂC–). H-NMR
(CDCl3) d: 1.85—2.15 (4H, m), 2.25—2.30 (2H, pentet, Jꢂ6.3 Hz), 2.85—
2.88 (2H, t, Jꢂ5.9 Hz), 2.95—2.98 (2H, t, Jꢂ5.9 Hz), 3.65—3.70 (2H, t,
Jꢂ6.2 Hz), 3.90—3.93 (2H, t, Jꢂ6.2 Hz), 4.14 (2H, s), 5.62 (1H, s), 8.30—
8.32 (2H, d, Jꢂ3.6 Hz), 8.55—8.75 (2H, d, Jꢂ3.7 Hz). MS m/z: 388.5
(Mꢃꢃ1). Anal. Calcd for C20H22N3SOCl: C, 61.65; H, 5.35; N, 10.57.
Found: C, 61.93; H, 5.67; N, 10.83.
2-(2-Pyridyl)-4-[(3-hydroxy)propyl]amino-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine (4f) Reaction time: 10 s. Yield 87%; colorless
needles; mp 205—206 °C; IR (KBr) cmꢀ1: 3366 (–OH), 3126 (–NH), 2946
1
(–CH2), 3014 (Ar-H), 1071 (–C–N). H-NMR (CDCl3) d: 1.83—2.17 (4H,
2-(2-Pyridyl)-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4[3H]-
one (2f) Reaction time: 150 s. Yield 72%; colorless needles; mp 302—
304 °C; IR (KBr) cmꢀ1: 3470 (NH), 3010 (Ar), 1670 (CꢂO. 1H-NMR
(CDCl3) d: 1.68—1.89 (4H, m), 2.67—2.98 (4H, m), 8.21—9.10 (4H, m),
11.2 (1H, br-s, D2O exchangeable). MS m/z: 284 (Mꢃꢃ1). Anal. Calcd for
C15H13N3SO: C, 63.60; H, 4.59; N, 14.84. Found: C, 63.35; H, 4.85; N,
15.10.
2-Substituted-4-chloro-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrim-
idines 3a—f. General Procedure A mixture of compound 2a—f (5
mmol) and phosphorus oxychloride (5 mmol) were taken in a 5 ml mi-
crowave reaction vial equipped with a magnetic stir bar. The reaction mix-
ture was irradiated in the microwave at 120 °C for 10 min. The reaction mix-
ture was poured into crushed ice and neutralized with sodium bicarbonate
solution. The solid thus obtained was collected and dried. The compound
was taken to next step immediately without any purification.
2-Substituted-4-[(3-hydroxy)propyl]amino-5,6,7,8-tetrahydrobenzo-
[b]thieno[2,3-d]pyrimidines 4a—f. General Procedure A mixture of
compound 3a—f (5 mmol), 3-aminopropanol (5 mmol) and triethylamine
(0.01 ml) were taken in a 5 ml microwave reaction vial equipped with a mag-
netic stir bar. The reaction mixture was irradiated in the microwave oven at
120 °C for 10 to 30 s. The reaction mixture was poured into a beaker con-
taining crushed ice and neutralized with dilute hydrochloric acid. The solid
thus obtained was filtered, dried and crystallized from toluene to give the tar-
get compounds 4a—f in good yields.
m), 2.23—2.29 (2H, pentet, Jꢂ6.2 Hz), 2.84—2.86 (2H, t, Jꢂ5.8 Hz),
2.93—2.95 (2H, t, Jꢂ5.8 Hz), 3.69—3.72 (2H, t, Jꢂ6.1 Hz), 3.88—3.93
(2H, t, Jꢂ6.2 Hz), 5.56 (1H, s), 8.28—8.29 (2H, d, Jꢂ3.4 Hz), 8.56—8.71
(2H, d, Jꢂ3.5 Hz). MS m/z: 341 (Mꢃꢃ1). Anal. Calcd for C18H20N4SO: C,
63.15; H, 5.65; N, 16.17. Found: C, 63.52; H, 5.88; N, 16.47.
6-Substituted-2,3,4-trihydropyrimido[1,2-c]9,10,11,12-tetrahydrobenzo-
[b]thieno[3,2-e]pyrimidines 5a—f. General Procedure Compound 4a—
f (5 mmol) coated on to silica gel # 60/120 was taken into a 5 ml microwave
reaction vial equipped with a magnetic stir bar. To the coated silica gel,
phosphorus oxychloride (5 mmol) was added. The reaction vessel was
capped and irradiated in the microwave oven (CEM, Discover) at 120 °C for
10 to 30 s. The reaction mixture was poured into crushed ice and neutralized
with sodium bicarbonate. The compound thus obtained was extracted with
ethylacetate, dried and distilled of the excess of solvent to get the target
compounds 5a—f in good yields. The compound was purified by recrystal-
lization from benzene.
6-Methyl-2,3,4-trihydropyrimido[1,2-c]9,10,11,12-tetrahydrobenzo[b]-
thieno[3,2-e]pyrimidine (5a) Reaction time: 15 s. Yield 85%; colorless
needles; mp 174—176 °C; IR (KBr) cmꢀ1: 2926 (–CH2), 3014 (–CH3), 1620
1
(–CꢂC–). H-NMR (CDCl3) d: 1.64—1.66 (2H, pentet, Jꢂ4.9 Hz), 1.71—
1.73 (2H, pentet, Jꢂ4.9 Hz), 1.79—1.83 (2H, pentet, Jꢂ5.9 Hz), 2.28 (3H,
s), 2.62—2.63 (2H, t, Jꢂ4.8 Hz), 2.79—2.82 (2H, t, Jꢂ4.8 Hz), 3.34—3.36
(2H, t, Jꢂ5.9 Hz), 3.82—3.85 (2H, t, Jꢂ5.8 Hz). MS m/z: 260 (Mꢃꢃ1).
Anal. Calcd for C14H17N3S: C, 64.55; H, 6.15; N, 15.98. Found: C, 64.86; H,
6.56; N, 16.21.
2-Methyl-4-[(3-hydroxy)propyl]amino-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine (4a) Reaction time: 30 s. Yield 91%; colorless
needles; mp 152—154 °C; IR (KBr) cmꢀ1: 3394 (–OH), 3243 (–NH), 2926
6-Ethyl-2,3,4-trihydropyrimido[1,2-c]9,10,11,12-tetrahydrobenzo[b]-
thieno[3,2-e]pyrimidine (5b) Reaction time: 20 s. Yield 55%; colorless
1
1
needles; mp 176—178 °C; IR (KBr) cmꢀ1: 3014 (alkyl), 1076 (C–N). H-
(–CH2), 3014 (CH3), 1076 (–C–N). H-NMR (CDCl3) d: 1.75—1.82 (4H,
m), 1.94—2.01 (2H, pentet, Jꢂ5.7 Hz,), 2.35 (3H, S), 2.69—2.71 (2H, t,
Jꢂ5.9 Hz), 2.91—2.94 (2H, t, Jꢂ4.8 Hz), 3.49—3.56 (2H, t, Jꢂ5.8 Hz),
3.83—3.86 (2H, t, Jꢂ5.7 Hz), 5.03 (1H, s), 5.52 (1H, s). MS m/z: 278
(Mꢃꢃ1). Anal. Calcd for C14H19N3SO: C, 60.34; H, 6.55; N, 14.96. Found:
C, 60.64; H, 6.85; N, 15.16.
NMR (CDCl3) d: 1.38—1.43 (3H, t, Jꢂ7.5 Hz), 1.85—1.99 (4H, m), 2.18—
2.28 (2H, pentet, Jꢂ6.2 Hz), 2.75—2.85 (2H, t, Jꢂ5.7 Hz), 2.92—2.98 (2H,
t, Jꢂ5.6 Hz), 3.02—3.08 (2H, q, Jꢂ7.5 Hz), 3.63—3.73 (2H, t, Jꢂ6.0 Hz),
3.87—3.97 (2H, t, Jꢂ6.0 Hz). MS m/z: 274 (Mꢃꢃ1). Anal. Calcd for
C15H19N3S: C, 65.76; H, 6.65; N, 15.20. Found: C, 65.93; H, 6.95; N, 15.38.
6-Benzyl-2,3,4-trihydropyrimido[1,2-c]9,10,11,12-tetrahydrobenzo[b]-
thieno[3,2-e]pyrimidine (5c) Reaction time: 30 s. Yield 70%; colorless
needles; mp 120—122 °C; IR (KBr) cmꢀ1: 2933 (–CH2), 3025 (Ar-H), 1621
2-Ethyl-4-[(3-hydroxy)propyl]amino-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine (4b) Reaction time: 30 s. Yield 60%; colorless
needles; mp 144—146 °C; IR (KBr) cmꢀ1: 3394 (–OH), 3243 (–NH), 2926
1
1
(–CH2), 3014 (CH3), 1076 (–C–N). H-NMR (CDCl3) d: 1.38—1.43 (3H, t,
(CꢂC), 1071 (C–N). H-NMR (CDCl3) d: 2.16—2.20 (4H, m), 2.49—2.53
Jꢂ7.5 Hz), 1.85—1.99 (4H, m), 2.19—2.29 (2H, pentet, Jꢂ6.2 Hz), 2.75—
2.85 (2H, t, Jꢂ5.7 Hz), 2.93—2.95 (2H, t, Jꢂ5.6 Hz), 3.02—3.08 (2H, q,
Jꢂ7.4 Hz), 3.67—3.71 (2H, t, Jꢂ6.1 Hz), 3.87—3.95 (2H, t, Jꢂ6.0 Hz),
5.49 (1H, s). MS m/z: 292 (Mꢃꢃ1). Anal. Calcd for C15H21N3SO: C, 61.76;
H, 7.05; N, 14.10. Found: C, 61.85; H, 7.21; N, 14.43.
(2H, pentet, Jꢂ6.4 Hz), 2.79 (2H, t, Jꢂ5.8 Hz), 2.98 (2H, t, Jꢂ5.9 Hz),
3.73—3.77 (4H, m), 4.10 (2H, s), 7.45—8.25 (5H, m). MS m/z: 336
(Mꢃꢃ1). Anal. Calcd for C20H21N3S: C, 71.35; H, 6.21; N, 13.31. Found: C,
71.64; H, 6.26; N, 12.53.
6-Phenyl-2,3,4-trihydropyrimido[1,2-c]9,10,11,12-tetrahydrobenzo[b]-
thieno[3,2-e]pyrimidine (5d) Reaction time: 20 s. Yield 80%; colorless
needles; mp 168—170 °C; IR (KBr) cmꢀ1: 2929 (–CH2), 3014 (Ar-H), 1655
2-Benzyl-4-[(3-hydroxy)propyl]amino-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine (4c) Reaction time: 25 s. Yield 92%; colorless
needles; mp 206—208 °C; IR (KBr) cmꢀ1: 3400 (–OH), 3355 (–NH), 2924
1
(CꢂC), 1048 (C–N). H-NMR (CDCl3) d: 2.13—2.19 (4H, m), 2.48—2.51
1
(–CH2), 3016 (Ar-H), 1048 (–C–N), 1650 (–CꢂC–). H-NMR (CDCl3) d:
(2H, pentet, Jꢂ6.4 Hz), 2.77 (2H, t, Jꢂ5.7 Hz), 2.96 (2H, t, Jꢂ5.7 Hz),
3.73—3.77 (4H, m), 7.45—7.55 (3H, m), 8.37—8.39 (2H, d, Jꢂ4.9 Hz). MS
m/z: 322 (Mꢃꢃ1). Anal. Calcd for C19H19N3S: C, 71.35; H, 6.21; N, 13.31.
Found: C, 71.02; H, 5.91; N, 13.08.
1.88—1.98 (4H, m), 2.23—2.30 (2H, pentet, Jꢂ6.2 Hz), 2.74—2.82 (2H, t,
Jꢂ5.7 Hz), 2.91—2.96 (2H, t, Jꢂ5.7 Hz), 3.65—3.74 (2H, t, Jꢂ6.2 Hz),
3.88—3.92 (2H, t, Jꢂ6.2 Hz), 4.11 (2H, s), 5.47 (1H, s), 7.41—7.50 (5H,
m). MS m/z: 354 (Mꢃꢃ1). Anal. Calcd for C20H23N3SO: C, 67.66; H, 6.25;
N, 11.65. Found: C, 67.98; H, 6.51; N, 11.89.
6-(p-Chlorobenzyl)-2,3,4-trihydropyrimido[1,2-c]9,10,11,12-tetrahy-
drobenzo[b]thieno[3,2-e]pyrimidine (5e) Reaction time: 10 s. Yield 68
%; colorless needles; mp 90—92 °C; IR (KBr) cmꢀ1: 2933 (–CH2), 3025
2-Phenyl-4-[(3-hydroxy)propyl]amino-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine (4d) Reaction time: 20 s. Yield 90%; colorless
1
(Ar-H), 1621 (CꢂC), 1071 (C–N). H-NMR (CDCl3) d: 1.94—2.28 (4H,