Synthesis of a series of novel thieno-and benzothieno[3,2-d]pyrimidin-4(3H) -ones

Article abstract of DOI:10.1055/s-0030-1258469

A series of novel thieno- and benzothieno[3,2-d]pyrimidin-4(3H)-ones is synthesised via condensation of 3-amino(benzo)thiophene-2-carboxylates with various lactams. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258469

1314
PAPER
Synthesis of a Series of Novel Thieno- and Benzothieno[3,2-d]pyrimidin-4(3H)-
ones
Thieno-
s
and Benzo
m
thieno[3,2-
d
]pyrim
a
idin-4(3
H
)
-
i
ones l Abdillahi, Gilbert Kirsch*
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843, 1 Boulevard Arago,
57070 Metz, France
Fax +33(3)87325801; E-mail: kirsch@univ-metz.fr
Received 15 December 2010; revised 3 February 2011
Ethyl 3-amino-2-thiophene-carboxylates 1a–d were pre-
Abstract: A series of novel thieno- and benzothieno[3,2-d]pyrimi-
pared by condensation of b-substituted b-chloroacryloni-
din-4(3H)-ones is synthesised via condensation of 3-amino(ben-
triles with sodium sulfide and ethyl bromoacetate as
zo)thiophene-2-carboxylates with various lactams.
previously described4–6 (Scheme 2).
Key words: thieno[3,2-d]pyrimidin-4(3H)-ones, benzothieno[3,2-
d]pyrimidin-4(3H)-ones, 3-aminothiophene-2-carboxylate, 3-ami- We also prepared methyl 3-amino-benzo[b]thiophene-2-
no benzothiophene-2-carboxylate
carboxylate (1f) and its 5-nitro derivative 1e by direct
condensation of the corresponding 2-chlorobenzonitrile
with methyl thioglycolate under basic conditions
(Scheme 3), using the method described earlier for the
In continuation of our work utilizing 3-amino-2-substitut-
ed thiophenes as starting materials,1 we report herein the
synthesis of several thieno[3,2-d]pyrimidin-4(3H)-ones
and benzothieno[3,2-d]pyrimidin-4(3H)-ones as novel,
potentially bioactive compounds.
displacement of a nitro group.7
R
R
i
NH2
CN
Thieno[2,3-d]pyrimidinones, prepared from ethyl 2-ami-
nothiophene-3-carboxylate as described in the literature,
have been developed for their biological activity against
breast cancer.2 The preparation of the previously un-
known isomeric [3,2-d]pyrimidin-4(3H)-ones are de-
S
CO2Me
Cl
1e R = NO2 35%
1f R = H 94%
Scheme 3 Reagents and conditions: (i) NaOMe, DMF, methyl thio-
glycolate, 60 °C, 3 h.
scribed
herein
from
ethyl
or
methyl
3-
amino(benzo)thieno-2-carboxylates 1a–f by condensation
with various lactams in the presence of phosphorus oxy-
chloride.3
Most of the lactams used in this work were commercially
available. However, 3,4-dihydro-2-(1H)quinolone (used
in the synthesis of compounds 2s and 2t) was prepared in
65% yield by Beckmann rearrangement of the oxime of
indanone.8
R2
R2
N
NH2
i
R1
N
Heating 3-amino(benzo)thieno-2-carboxylates 1a–f with
phosphorus oxychloride at reflux temperature in anhy-
drous dichloroethane in the presence of different lactams
afforded the corresponding pyrimidinones 2a–r in moder-
ate to good yields (Table 1). Products 2s,t were obtained
by condensation between 3-aminobenzo[b]thiophenes
1e,f and 3,4-dihydro-2-(1H)quinolone.
R1
CO2R3
S
S
O
1a–f
2a–t
R1 = aryl, R2 = H
R1 = R2 = cycloalkyl
Scheme 1 Reagents and conditions: (i) lactam, DCE, POCl3, 3 h.
The nitro derivatives 2m–o were reduced into the corre-
sponding aminobenzothieno[3,2-d]pyrimidinones 3a–c
using tin(II) chloride dihydrate in N,N-dimethylform-
amide9 in moderate yields (Scheme 4).
R2
NH2
O
R2
R1
R2
R1
CN
Cl
iv
i, ii, iii
R1
CO2Et
S
1a–d
H2N
O2N
Scheme 2 Reagents and conditions: (i) POCl3, DMF, 60 °C, 5 h; (ii)
NH2OH·HCl, EtOH; (iii) Ac2O, reflux; (iv) Na2S·9H2O, DMF,
BrCH2CO2Et, 60 °C, 3 h.
N
N
i
n
n
N
N
S
S
O
O
2m–o
3a n = 1 50%
3b n = 2 44%
3c n = 3 52%
SYNTHESIS 2011, No. 8, pp 1314–1318
x
x
.
x
x
.2
0
1
1
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1258469; Art ID: Z54010SS
Scheme 4 Reagents and conditions: (i) SnCl2·2H2O, DMF, r.t.
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thieno- and Benzothieno[3,2-d]pyrimidin-4(3H)-ones
1315
Table 1 Structures and Yields of Thieno- and Benzothieno[3,2-d]pyrimidinones 2a–t
Substrate
Lactam
Product
Yield (%)
NH2
N
2a
2b
2c
n = 1
n = 2
n = 3
77
60
69
O
CO2Et
N
S
n
S
HN
O
1a
NH2
N
2d
2e
2f
n = 1
n = 2
n = 3
50
68
50
O
CO2Et
n
Cl
N
S
n
S
HN
O
Cl
1b
NH2
N
2g
2h
2i
n = 1
n = 2
n = 3
60
66
63
CO2Et
O
n
N
S
n
HN
O2N
S
O
O2N
1c
NH2
N
2j
2k
2l
n = 1
n = 2
n = 3
30
42
51
O
n
N
CO2Et
n
S
HN
S
O
1d
O2N
NH2
2m
2n
2o
n = 1
n = 2
n = 3
53
36
55
O2N
O
N
O
CO2Me
n
HN
n
S
N
S
1e
NH2
N
2p
2q
2r
n = 1
n = 2
n = 3
88
60
93
O
n
N
CO2Me
NH2
n
HN
S
S
O
1f
O2N
N
O2N
2s
2t
57
47
N
O
CO2Me
N
H
O
O
S
S
1e
NH2
N
N
O
CO2Me
N
H
S
S
1f
Thieno- and Benzothieno[3,2-d]pyrimidinones; General Proce-
dure
In conclusion, novel (benzo)thieno[3,2-d]pyrimidinones
were synthesized in moderate to good yields from ethyl or
methyl 3-amino(benzo)thieno-2-carboxylates by conden-
sation with various lactams in the presence of phosphorus
oxychloride. Amines 3a–c were prepared by reduction of
the corresponding nitro derivatives.
POCl3 (1.4 mL, 2.3 g, 1.5 equiv) was added dropwise to a mixture
of methyl or ethyl 3-aminothieno- or benzothiophene-2-carboxylate
(10 mmol) and the appropriate lactam (1.5 equiv) in anhyd DCE
(200 mL). The mixture was heated at reflux temperature until no
starting material was detected by TLC (1.5–3 h, 10% EtOAc–
CH2Cl2). Approximately 80% of the solvent was evaporated, H2O
(100 mL) was added and the soln was made basic with 20% aq KOH
soln. The mixture was extracted with CH2Cl2 (3 × 20 mL), washed
with brine (20 mL) and H2O (20 mL), and dried (MgSO4). After fil-
tration, the solvent was evaporated. The solid obtained was recrys-
tallized from EtOH or MeOH.
Melting points were determined on a Stuart SMP3 apparatus and are
1
uncorrected. H and 13C NMR spectra were recorded on an AC
Bruker 250 MHz spectrometer in CDCl3 or DMSO-d6. HRMS was
accomplished using a MicroTof-Q 98 spectrometer.
Synthesis 2011, No. 8, 1314–1318 © Thieme Stuttgart · New York

1316
I. Abdillahi, G. Kirsch
PAPER
2-(4-Methylphenyl)-6,7-dihydropyrrolo[1,2-a]thieno[3,2-d]py-
rimidin-9(5H)-one (2a)
Yellow solid; yield: 77%; mp 213 °C.
2-(4-Chlorophenyl)-6,7,8,9-tetrahydrothieno[3¢,2¢:4,5]pyrimi-
do[1,2-a]azepin-11(5H)-one (2f)
Brown solid; yield: 50%; mp 160 °C.
1H NMR (CDCl3): d = 2.25–2.37 (m, 2 H, CH2), 2.41 (s, 3 H, CH3),
3.14–3.21 (t, J = 7.9 Hz, 2 H, CH2), 4.19–4.25 (t, J = 7.2 Hz, 2 H,
CH2), 7.22–7.25 (d, J = 8.0 Hz, 2 H, 2CH), 7.38 (s, 1 H, CH), 7.56–
7.60 (d, J = 8.0 Hz, 2 H, 2CH).
13C NMR (CDCl3): d = 19.8, 21.3, 32.2, 46.6, 119.4, 120.0, 126.2,
126.3, 129.8, 130.5, 139.7, 152.5, 157.0, 158.8, 161.4.
1H NMR (CDCl3): d = 1.85 (m, 6 H, 2CH2), 3.07 (m, 2 H, CH2),
4.41 (m, 2 H, CH2), 7.36 (s, 1 H, CH), 7.38–7.39 (d, J = 10.8 Hz, 2
H, 2CH), 7.57–7.62 (d, J = 10.8 Hz, 2 H, 2CH).
13C NMR (CDCl3): d = 23.5, 27.7, 29.8, 37.7, 42.7, 120.5, 127.6,
129.5, 131.8, 135.3, 151.0, 156.6, 157.8, 161.8.
HRMS (APCI): m/z [M + H]+ calcd for C17H16ClN2OS: 331.0666;
found: 331.0687.
HRMS (APCI): m/z [M + H]+ calcd for C16H15N2OS: 283.0860;
found: 283.1225.
2-(4-Nitrophenyl)-6,7-dihydropyrrolo[1,2-a]thieno[3,2-d]pyri-
midin-9(5H)-one (2g)
Yellow solid; yield: 60%; mp 300 °C.
2-(4-Methylphenyl)-5,6,7,8-tetrahydro-10H-pyrido[1,2-
a]thieno[3,2-d]pyrimidin-10-one (2b)
Beige solid; yield: 60%; mp 220 °C.
1H NMR (CDCl3): d = 2.25–2.34 (m, 2 H, CH2), 3.11–3.18 (t,
J = 7.5 Hz, 2 H, CH2), 4.15–4.21 (t, J = 7.5 Hz, 2 H, CH2), 7.50 (s,
1 H, CH), 7.76–7.79 (d, J = 8.6 Hz, 2 H, 2CH), 8.22–8.26 (d, J = 8.6
Hz, 2 H, 2CH).
13C NMR (CDCl3): d = 19.8, 32.2, 46.9, 122.2, 124.5, 127.0, 139.1,
148.0, 149.0, 156.6, 157.8, 162.2.
1H NMR (CDCl3): d = 1.92–2.02 (m, 4 H, 2CH2), 2.36 (s, 3 H,
CH3), 2.96–3.02 (t, J = 6.5 Hz, 2 H, CH2), 4.07–4.11 (t, J = 5.7 Hz,
2 H, CH2), 7.22–7.25 (d, J = 7.5 Hz, 2 H, 2CH), 7.35 (s, 1 H, CH),
7.56–7.59 (d, J = 7.5 Hz, 2 H, 2CH).
13C NMR (CDCl3): d = 19.3, 21.3, 22.0, 31.7, 42.2, 119.2, 119.8,
125.8, 126.3, 129.8, 130.5, 134.4, 139.6, 152.6, 156.6, 156.8, 158.1.
HRMS (APCI): m/z [M + H]+ calcd for C15H12N3O3S: 314.0594;
found: 314.0594.
HRMS (APCI): m/z [M + H]+ calcd for C17H17N2OS: 297.1056;
found: 297.1062.
2-(4-Nitrophenyl)-5,6,7,8-tetrahydro-10H-pyrido[1,2-
a]thieno[3,2-d]pyrimidin-10-one (2h)
Yellow solid; yield: 66%; mp 250 °C.
2-(4-Methylphenyl)-6,7,8,9-tetrahydrothieno[3¢,2¢:4,5]pyrimi-
do[1,2-a]azepin-11(5H)-one (2c)
Beige solid; yield: 69%; mp 230 °C.
1H NMR (CDCl3): d = 1.95–2.08 (m, 4 H, 2CH2), 3.02–3.07 (t,
J = 6.5 Hz, 2 H, CH2), 4.01–4.15 (t, J = 6.5 Hz, 2 H, CH2), 7.55 (s,
1 H, CH), 7.83–7.86 (d, J = 8.8 Hz, 2 H, 2CH), 8.26–8.32 (d, J = 8.8
Hz, 2 H, 2CH)
13C NMR (CDCl3): d = 19.1, 21.9, 31.5, 42.5, 122.2, 124.5, 127.0,
139.2, 147.9, 148.9, 157.5, 157.8.
1H NMR (CDCl3): d = 1.74–1.84 (m, 6 H, 3CH2), 2.36 (s, 3 H,
CH3), 3.05–3.09 (m, 2 H, CH2), 4.39–4.42 (m, 2 H, CH2), 7.22–7.25
(d, J = 8.0 Hz, 2 H, 2CH), 7.36 (s, 1 H, CH), 7.56–7.59 (d, J = 8.0
Hz, 2 H, 2CH).
13C NMR (CDCl3): d = 21.3, 25.9, 26.6, 27.1, 30.4, 44.6, 125.3,
125.8, 129.6, 130.7, 144.1, 148.1, 154.5, 156.6, 160.1.
HRMS (APCI): m/z [M + H]+ calcd for C16H14N3O3S: 328.0765;
found: 328.0750.
HRMS (APCI): m/z [M + H]+ calcd for C18H19N2OS: 311.1173;
found: 311.1196.
2-(4-Nitrophenyl)-6,7,8,9-tetrahydrothieno[3¢,2¢:4,5]pyrimi-
do[1,2-a]azepin-11(5H)-one (2i)
Brown solid; yield: 63%; mp 236 °C.
2-(4-Chlorophenyl)-6,7-dihydropyrrolo[1,2-a]thieno[3,2-d]py-
rimidin-9(5H)-one (2d)
Brown solid; yield: 50%; mp 240 °C.
1H NMR (CDCl3): d = 1.87–1.93 (m, 6 H, 3CH2), 3.09–3.13 (m, 2
H, CH2), 4.42–4.46 (m, 2 H, CH2), 7.53 (s, 1 H, CH), 7.84–7.85 (d,
J = 4.2 Hz, 2 H, 2CH), 8.29–8.31 (d, J = 4.2 Hz, 2 H, 2CH).
13C NMR (CDCl3): d = 25.1, 27.7, 29.5, 37.5, 42.8, 122.7, 124.0,
127.7, 139.3, 147.9, 148.8, 156.4, 157.8, 162.2.
HRMS (APCI): m/z [M + H]+ calcd for C17H16N3O3S: 342.0907;
found: 342.0898.
1H NMR (CDCl3): d = 2.26–2.38 (q, J = 7.8 Hz, 2 H, CH2), 3.15–
3.21 (t, J = 7.8 Hz, 2 H, CH2), 4.19–4.25 (t, J = 7.8 Hz, 2 H, CH2),
7.37 (s, 1 H, CH), 7.40–7.42 (d, J = 4.2 Hz, 2 H, 2CH), 7.60–7.62
(t, J = 4.2 Hz, 2 H, 2CH).
13C NMR (CDCl3): d = 19.8, 32.2, 46.6, 120.3, 120.6, 127.5, 129.3,
130.0, 131.7, 135.0, 135.4, 150.7, 156.9, 158.7, 161.7.
HRMS (APCI): m/z [M + H]+ calcd for C15H12ClN2OS: 303.0353;
found: 303.0373.
5,6,9,10-Tetrahydronaphtho[2¢,1¢:4,5]thieno[3,2-d]pyrrolo[1,2-
a]pyrimidin-12(8H)-one (2j)
2-(4-Chlorophenyl)-5,6,7,8-tetrahydro-10H-pyrido[1,2-
a]thieno[3,2-d]pyrimidin-10-one (2e)
Brown solid; yield: 68%; mp 191 °C.
1H NMR (CDCl3): d = 1.91–2.05 (m, 4 H, 2CH2), 2.96–3.01 (t,
J = 6.6 Hz, 2 H, CH2), 4.06–4.10 (t, J = 6.0 Hz, 2 H, CH2), 7.34 (s,
1 H, CH), 7.36–7.40 (d, J = 8.5 Hz, 2 H, 2CH), 7.57–7.60 (d, J = 8.5
Hz, 2 H, 2CH).
Brown solid; yield: 30%; mp 286 °C.
1H NMR (CDCl3): d = 2.31–2.35 (m, 2 H, CH2), 3.02–3.06 (m, 4 H,
2CH2,), 3.19–3.23 (t, J = 7.5 Hz, 2 H, CH2), 4.25–4.29 (t, J = 7.5
Hz, 2 H, CH2), 7.27–7.31 (m, 3 H, 3CH), 7.48–7.52 (m, 1 H, CH).
13C NMR (CDCl3): d = 20.0, 21.3, 28.4, 32.3, 46.6, 119.6, 123.8,
127.2, 128.3, 129.0, 130.6, 132.0, 136.4, 144.4, 156.5, 157.3, 161.4.
HRMS (APCI): m/z [M + H]+ calcd for C17H15N2OS: 295.0860;
found: 295.0900.
13C NMR (CDCl3): d = 19.2, 22.0, 31.6, 42.3, 120.2, 127.7, 129.3,
131.8, 135.3, 150.8, 156.7, 156.9, 158.0.
HRMS (APCI): m/z [M + H]+ calcd for C16H14ClN2OS: 317.0510;
found: 317.0526.
5,6,8,9,10,11-Hexahydro-13H-naphtho[2¢,1¢:4,5]thieno[3,2-
d]pyrido[1,2-a]pyrimidin-13-one (2k)
Brown solid; yield: 42%; mp 245 °C.
Synthesis 2011, No. 8, 1314–1318 © Thieme Stuttgart · New York

PAPER
Thieno- and Benzothieno[3,2-d]pyrimidin-4(3H)-ones
1317
1H NMR (CDCl3): d = 1.98–2.03 (m, 4 H, 2CH2), 3.01–3.07 (m, 6
H, 3CH2), 4.10–4.14 (m, 2 H, CH2), 7.27–7.32 (m, 3 H, 3CH), 7.50–
7.52 (d, J = 2.5 Hz, 1 H, CH).
13C NMR (CDCl3): d = 19.3, 21.1, 22.0, 28.5, 31.7, 42.1, 119.3,
123.9, 127.1, 128.3, 128.7, 130.6, 131.9, 136.4, 144.3, 154.5, 156.6,
158.4.
1H NMR (CDCl3): d = 2.27–2.39 (q, J = 7.5 Hz, 2 H, CH2), 3.21–
3.28 (t, J = 7.5 Hz, 2 H, CH2), 4.22–4.28 (t, J = 7.5 Hz, 2 H, CH2),
7.42–7.55 (m, 2 H, 2CH), 7.84–7.88 (d, J = 7.5 Hz, 1 H, CH), 8.21–
8.24 (d, J = 7.5 Hz, 1 H, CH).
13C NMR (CDCl3): d = 19.9, 32.3, 46.8, 121.0, 122.9 (2C), 123.8,
124.9, 134.1, 141.5, 153.8, 157.6, 161.8.
HRMS (APCI): m/z [M + H]+ calcd for C18H17N2OS: 309.1056;
HRMS (APCI): m/z [M + H]+ calcd for C13H11N2OS: 243.0590;
found: 309.1069.
found: 243.0587.
5,6,9,10,11,12-Hexahydronaph-
tho[2¢¢,1¢¢:4¢,5¢]thieno[3¢,2¢:4,5]pyrimido[1,2-a]azepin-14(8H)-
one (2l)
8,9,10,11-Tetrahydro-6H[1]benzothieno[3,2-d]pyrido[1,2-a]py-
rimidin-6-one (2q)
Yellow solid; yield: 60%; mp 149 °C.
Beige solid; yield: 51%; mp 235 °C.
1H NMR (CDCl3): d = 1.90–2.02 (m, 4 H, 2CH2), 3.02–3.07 (t,
J = 5.0 Hz, 2 H, CH2), 4.07–4.12 (t, J = 5.0 Hz, 2 H, CH2), 7.40–
7.54 (m, 2 H, 2CH), 7.82–7.85 (d, J = 7.5 Hz, 1 H, CH), 8.19–8.23
(d, J = 7.5 Hz, 1 H, CH).
1H NMR (CDCl3): d = 1.85–1.90 (m, 6 H, 3CH2), 3.01–3.05 (m, 4
H, 2CH2), 3.09–3.13 (m, 2 H, CH2), 4.42–4.46 (m, 2 H, CH2), 7.28–
7.33 (m, 3 H, 3CH), 7.49–7.51 (d, J = 2.5 Hz, 1 H, CH).
13C NMR (CDCl3): d = 21.1, 25.3, 27.8, 28.5, 29.6, 37.5, 42.7,
119.7, 123.9, 127.1, 128.3, 128.9, 130.7, 132.3, 136.4, 144.4, 154.5,
158.2, 161.4.
13C NMR (CDCl3): d = 20.9, 22.3, 31.6, 42.5, 20.6, 123.8 (2C),
124.9, 128.3, 134.5, 151.9, 157.0, 158.9, 162.9.
HRMS (APCI): m/z [M + H]+ calcd for C14H13N2OS: 257.0743;
found: 257.0747.
HRMS (APCI): m/z [M + H]+ calcd for C19H19N2OS: 323.1213;
found: 323.1216.
9,10,11,12-Tetrahydro[1]benzothieno[3¢,2¢:4,5]pyrimido[1,2-
a]azepin-6(8H)-one (2r)
Beige solid; yield: 93%; mp 165 °C
9-Nitro-2,3-dihydro[1]benzothieno[3,2-d]pyrrolo[1,2-a]pyrimi-
din-5(1H)-one (2m)
Yellow solid; yield: 53%; mp 303 °C.
1H NMR (CDCl3): d = 1.71–1.85 (m, 6 H, 3CH2), 3.13–3.20 (m, 2
H, CH2), 4.43–4.46 (m, 2 H, CH2), 7.44–7.56 (m, 2 H, 2CH), 7.86–
7.89 (d, J = 7.5 Hz, 1 H, CH), 8.24–8.28 (d, J = 7.5 Hz, 1 H, CH).
13C NMR (CDCl3): d = 25.3, 27.7, 29.4, 30.6, 37.5, 43.0, 121.2,
123.6, 123.9, 124.9, 141.7, 143.6, 151.8, 158.7, 161.9.
HRMS (APCI): m/z [M + H]+ calcd for C15H15N2OS: 271.0900;
found: 271.0902.
1H NMR (CDCl3): d = 2.36–2.48 (q, J = 7.5 Hz, 2 H, CH2), 3.29–
3.36 (t, J = 7.5 Hz, 2 H, CH2), 4.29–4.35 (t, J = 7.5 Hz, 2 H, CH2),
8.01–8.04 (d, J = 7.5 Hz, 1 H, CH), 8.39–8.43 (dd, J = 1.5, 7.5 Hz,
1 H, CH), 9.19–9.21 (d, J = 1.5 Hz, 1 H, CH).
13C NMR (CDCl3): d = 19.9, 32.3, 47.0, 119.6, 122.7, 123.5, 124.2,
134.5, 145.9, 147.0, 153.8, 157.2, 163.0.
HRMS (APCI): m/z [M + H]+ calcd for C13H10N3O3S: 288.0437;
found: 288.0447.
9-Nitro-5,6-dihydro-13H-[1]benzothieno[3¢,2¢:4,5]pyrimi-
do[1,2-a]quinolin-13-one (2s)
2-Nitro-8,9,10,11-tetrahydro-6H-[1]benzothieno[3,2-d]pyri-
do[1,2-a]pyrimidin-6-one (2n)
Yellow solid; yield: 36%; mp 262 °C.
1H NMR (CDCl3): d = 1.97–2.15 (m, 4 H, 2CH2), 3.10–3.15 (t,
J = 7.5 Hz, 2 H, CH2), 4.15–4.20 (t, J = 7.5 Hz, 2 H, CH2), 7.96–
8.00 (d, J = 9.0 Hz, 1 H, 1CH), 8.34–8.38 (dd, J = 2.3, 9.0 Hz, 1 H,
CH), 9.09–9.11 (d, J = 2.3 Hz, 1 H, CH).
13C NMR (CDCl3): d = 19.2, 22.0, 31.8, 42.9, 119.5, 122.70,
122.71, 124.1, 134.6, 145.8, 147.0, 151.8, 158.3, 158.4.
HRMS (APCI): m/z [M + H]+ calcd for C14H12N3O3S: 302.0594;
Yellow solid; yield: 57%; mp 290 °C.
1H NMR (CDCl3): d = 3.15–3.20 (m, 2 H, CH2), 4.49–4.54 (m, 2 H,
CH2), 7.33–7.36 (m, 1 H, CH), 7.50–7.60 (m, 2 H, 2CH), 8.04–8.07
(d, J = 7.5 Hz, 1 H, CH), 8.42–8.46 (dd, J = 2.5, 7.5 Hz, 1 H, CH),
8.62–8.66 (m, 1 H, CH), 9.28–9.29 (d, J = 2.5 Hz, 1 H, CH).
13C NMR (CDCl3): d = 19.3, 31.6, 46.6, 105.5, 118.5, 120.0, 123.8,
127.7, 135.2, 146.9, 152.9, 156.9, 162.3.
HRMS (APCI): m/z [M + H]+ calcd for C18H12N3O3S: 350.0594;
found: 350.0577.
found: 302.0611.
5,6-Dihydro-13H-[1]benzothieno[3¢,2¢:4,5]pyrimido[1,2-
a]quinolin-13-one (2t)
2-Nitro-9,10,11,12-tetrahydro[1]benzothieno[3¢,2¢:4,5]pyrimi-
do[1,2-a]azepin-6(8H)-one (2o)
Yellow solid; yield: 55%; mp 246 °C.
1H NMR (CDCl3): d = 1.81–1.86 (m, 6 H, 3CH2), 3.19–3.23 (m, 2
H, CH2), 4.46–4.50 (m, 2 H, CH2), 7.96–7.98 (d, J = 7.5 Hz, 1 H,
CH), 8.33–8.37 (dd, J = 2.3, 7.5 Hz, 1 H, CH), 9.05–9.07 (d, J = 2.3
Hz, 1 H, CH).
13C NMR (CDCl3): d = 25.1, 27.6, 29.6, 37.4, 43.2, 119.4, 122.6,
123.2, 124.0, 134.8, 145.7, 147.0, 151.6, 158.2, 163.1.
HRMS (APCI): m/z [M + H]+ calcd for C15H14N3O3S: 316.0750;
Beige solid; yield: 47%; mp 228 °C.
1H NMR (CDCl3): d = 3.10–3.16 (t, J = 7.5 Hz, 2 H, CH2), 4.48–
4.52 (t, J = 7.5 Hz, 2 H, CH2), 7.27–7.33 (m, 1 H, CH), 7.43–7.62
(m, 4 H, 4CH), 7.89–7.93 (m, 1 H, CH), 8.40–8.44 (m, 1 H, CH),
8.55–8.60 (m, 1 H, CH).
13C NMR (CDCl3): d = 27.3, 39.7, 121.5, 123.4, 123.8, 125.0,
127.5, 127.7, 127.9, 128.9, 129.4, 131.9, 134.7, 136.8, 141.6, 151.5,
152.3, 158.3.
HRMS (APCI): m/z [M + H]+ calcd for C18H13N2OS: 305.0743;
found: 305.0767.
found: 316.0754.
Amino-benzothieno[3,2-d]pyrimidinones; General Procedure
SnCl2·2H2O (14.9 mmol, 3.37 g) was added to nitro-benzo-
thieno[3,2-d]pyrimidinone 2m–o (0.5 mmol, 150 mg) in DMF (10
mL). The mixture was stirred at r.t. until no starting material was de-
tected by TLC (4 h, EtOAc–CHCl3, 3:1). The reaction mixture was
2,3-Dihydro[1]benzothieno[3,2-d]pyrrolo[1,2,-a]pyrimidin-
5(1H)-one (2p)
Beige solid; yield: 88%; mp 210 °C.
Synthesis 2011, No. 8, 1314–1318 © Thieme Stuttgart · New York

1318
I. Abdillahi, G. Kirsch
PAPER
poured in water and the solid obtained was filtered. The solid ob-
tained was recrystallized from EtOH or MeOH.
1H NMR (DMSO-d6): d = 1.70–1.76 (m, 6 H, 3CH2), 3.11–3.14 (m,
2 H, CH2), 4.35–4.38 (m, 2 H, CH2), 5.42 (s, 2 H, NH2), 6.92–6.96
(dd, J = 2.0, 8.5 Hz, 1 H, CH), 7.34–7.36 (d, J = 2.0 Hz, 1 H, CH),
7.66–7.69 (d, J = 8.5 Hz, 1 H, CH).
13C NMR (DMSO-d6): d = 24.6, 27.0, 28.8, 36.5, 42.0, 105.5,
118.5, 120.2, 123.7, 127.8, 135.4, 147.0, 150.8, 157.9, 161.9.
9-Amino-2,3-dihydro[1]benzothieno[3,2-d]pyrrolo[1,2-a]pyri-
midin-5(1H)-one (3a)
Yellow solid; yield: 50%; mp 275 °C.
1H NMR (DMSO-d6): d = 2.18–2.24 (m, 2 H, CH2), 3.11–3.17 (m,
2 H, CH2), 4.06–4.11 (m, 2 H, CH2), 5.39 (s, 2 H, NH2), 6.91–6.95
(m, 1 H, CH), 7.33 (s, 1 H, CH), 7.65–7.69 (m, 1 H, CH).
HRMS (APCI): m/z [M + H]+ calcd for C15H16N3OS: 286.100;
found: 286.100.
13C NMR (DMSO-d6): d = 19.3, 31.6, 46.6, 105.5, 118.5, 120.0,
123.8, 127.7, 135.2, 146.9, 152.9, 156.9, 162.3.
Acknowledgment
HRMS (APCI): m/z [M + H]+ calcd for C13H12N3OS: 258.0696;
We thank EGIDE for financial support to I.A.
found: 258.0695.
References
2-Amino-8,9,10,11-tetrahydro-6H-[1]benzothieno[3,2-d]pyri-
do[1,2-a]pyrimidin-6-one (3b)
(1) Migianu, E.; Kirsch, G. Synthesis 2002, 1096.
(2) Karkola, S.; Lilienkampf, A.; Wähälä, K. ChemMedChem
2008, 3, 461.
(3) Wähälä, K.; Lilienkampf, A.; Alho, S.; Huhtinen, K.;
Johansson, N.; Koskimies, P.; Vihko, K. WO2004110549,
2004; Chem. Abstr. 2004, 142, 74590.
Yellow solid; yield: 44%; mp 230 °C.
1H NMR (DMSO-d6): d = 1.84–1.97 (m, 4 H, 2CH2), 2.95–3.00 (t,
J = 7.5 Hz, 2 H, CH2), 3.96–4.01 (t, J = 7.5 Hz, 2 H, CH2), 5.28 (s,
2 H, NH2), 6.91–6.95 (dd, J = 2.5, 7.5 Hz, 1 H, CH), 7.35–7.36 (d,
J = 2.5 Hz, 1 H, CH), 7.57–7.61 (d, J = 7.5 Hz, 1 H, CH).
13C NMR (DMSO-d6): d = 15.8, 21.3, 31.1, 42.0, 105.8, 118.5,
(4) (a) Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119. (b)Arnold,
Z.; Sorm, F. Collect. Czech. Chem. Commun. 1958, 23, 452.
(5) Hartmann, H.; Liebscher, J. Synthesis 1984, 275.
(6) Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2007, 1027.
(7) Beck, R. J.; Yahner, J. A. J. Org. Chem. 1974, 39, 3440.
(8) (a) Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Bioorg. Med.
Chem. Lett. 2002, 12, 387. (b) Torisawa, Y.; Nishi, T.;
Minamikawa, J.-i. Bioorg. Med. Chem. 2003, 11, 2205.
(9) Carpenter, R. D.; Lam, K. S.; Kurth, M. J. J. Org. Chem.
2007, 72, 284.
119.7, 123.7, 127.9, 135.2, 146.7, 151.0, 157.3, 158.0.
HRMS (APCI): m/z [M + H]+ calcd for C14H14N3OS: 272.0852;
found: 272.0856.
2-Amino-9,10,11,12-tetrahydro[1]benzothieno[3¢,2¢:4,5]pyrimi-
do[1,2-a]azepin-6(8H)-one (3c)
Yellow solid; yield: 52%; mp 213 °C.
Synthesis 2011, No. 8, 1314–1318 © Thieme Stuttgart · New York