Synthesis of derivatives of pyrido[4,3-d]pyrimidin-4(3H)-one via an iminophosphorane

Article abstract of DOI:10.1002/hlca.200690133

A series of new, 2-substituted 3-aryl-8,9,10,11-tetrahydro-5-methyl[1] benzothieno[3′,2′:5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones, compounds 5a-q, were designed and synthesized via the aza-Wittig reaction as the key step. The iminophosphorane 1 reacted with

Full text of DOI:10.1002/hlca.200690133

Helvetica Chimica Acta – Vol. 89 (2006)
1337
Synthesis of Derivatives of Pyrido[4,3-d]pyrimidin-4(3H)-one via an
Iminophosphorane
by Jian-Chao Liu, Hong-Wu He*, Qing-Yun Ren, and Ming-Wu Ding
Key Laboratory of Pesticide & Chemical Biology of the Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan 430079, P. R. China
(phone: +86-27-67867960; e-mail: he1208@mail.ccnu.edu.cn)
A series of new, 2-substituted 3-aryl-8,9,10,11-tetrahydro-5-methyl[1]benzothieno[3’,2’:5,6]pyr-
ido[4,3-d]pyrimidin-4(3H)-ones, compounds 5a–q, were designed and synthesized via the aza-Wittig
reaction as the key step. The iminophosphorane 1 reacted with phenyl isocyanate (or 4-chlorophenyl iso-
cyanate) to the carbodiimide 4, which was cyclized to 5 upon addition of different amines, EtOH, or phe-
nols in the presence of a catalytic amount of EtONa or K2CO3 (Schemes 1 and 2). The structures of com-
pounds 5 were confirmed by IR, 1H- and 13C-NMR, EI-MS, elemental analyses, and, in the case of 5l, by
single-crystal X-ray diffraction (Figure).
Introduction. – The derivatives of pyridopyrimidines have attracted the interest of
pharmaceutical companies recently. This is due, in part, to the wide range of biological
activities associated with this heterocyclic scaffold. For example, some related 4-(phen-
ylamino)pyrido[d]pyrimidines have been reported as selective inhibitors of tyrosine
phosphorylation by the epidermal growth-factor receptor (EGFR), and have become
an important class of potential anticancer drugs [1][2]. The methods described so far
for the preparation of some representative derivatives of this ring system involve two
general routes: a) formation of the pyridine ring by cyclization of suitable substituents
of a pyrimidine [3][4]; b) formation of the pyrimidine ring by cyclization of a suitable
pyridine derivative [5]. Unfortunately, these methods often require forcing conditions,
long reaction times, and complex synthetic pathways.
The aza-Wittig reactions of iminophosphoranes have received increasing attention
in view of their utility in the synthesis of N-heterocyclic compounds [6]. Recently, we
have become interested in the synthesis of pyrazolopyrimidinones, thienopyrimidi-
nones, and pyridopyrimidinones from various iminophosphoranes, with the aim of eval-
uating their biological activities [7]. Here, we wish to report a facile synthesis of fused
pyridopyrimidine derivatives from the easily accessible iminophosphorane 1.
Results and Discussion. – The 5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine 2,
easily obtained from 2-amino-4,5,6,7-tetrahydro[1]benzothiophene-3-carbonitrile (3)
and ethyl acetoacetate (=ethyl 3-oxobutanoate) in the presence of SnCl4, was con-
verted to the iminophosphorane 1 via reaction with Ph3
N
N
(Scheme 1).
The iminophosphorane 1 reacted with phenyl isocyanate (or 4-chlorophenyl isocy-
anate) to the carbodiimide 4. In refluxing toluene, 4 did not react with alkylamines to
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 1
Table. Substituents, Physico-Chemical Data, and Synthetic Details for Compounds 5
No.
R1
R2
U
Ar
Formula
M.p. [ 8]
Reaction
time [h]
Yield
[%]a)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
PrNH
i-PrNH
BuNH
Et(Me)CHNH
t-BuNH
Furfurylaminob)
C6
C
G
C23
C23H24
C24H26N4
C24H26N4
C24H26N4
C25H22N4
C25H28N4
C24H26N4
C25H26N4
C28H34N4
C26H30N4
G
G
U
243–244
209–211
233–234
242–244
213–214
250–251
202–204
>300
263–264
142–143
194–195
228–230
238–240
273–275
186–189
217–218
240–241
11
11
11
11
11
11
11
13
13
13
13
12
14
11
14
14
14
65
58
72
80
66
72
54
57
69
67
59
82
89
71
39
91
95
C6H5
C6
C
6H5
C6
C6
C6
C
N
Me
Et2N
Piperidin-1-yl
Bu2N
Pr2N
C
NH
T
6H5
U
C6
C6
4-Cl-C6
4-Cl-C
4-Cl-C
A
PrNH
i-PrNH
BuNH
EtO
G
C23H23ClN4OS
C23H23ClN4OS
C24H25ClN4OS
6H5
C
C6H5
C22
C26H21
C26H20ClN3
A
N
S
C
N
G
C6
C6
A
N
A
H5
O
A
N
G
E
b
a) Yields of isolated products based on 1. ) (Furan-2-ylmethyl)amino.
the target compounds. However, in CH2Cl2 and in the presence of a catalytic amount of
EtONa, compounds 4 were converted smoothly to the 2-(alkylamino)-8,9,10,11-tetra-
hydrobenzo[4’,5’]thieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones 5a–n in satisfac-
tory yields at room temperature (Table). Irrespective of whether primary or secondary
amines were used, the cyclization proceeded very smoothly.
The reaction of the carbodiimide 4 with phenols (or with EtOH) in MeCN did not
lead to the desired 2-(aryloxy)- or 2-ethoxy-substituted congeners 5. However, when
carried out in the presence of catalytic amounts of K2CO3, the reaction took place to
give 5o–q in good yields (Scheme 2).

Helvetica Chimica Acta – Vol. 89 (2006)
1339
Scheme 2
Figure. ORTEP Plot [11] of the molecular structure of 5l (50% probability ellipsoids, arbitrary atom
numbering)
All products of type 5 were obtained as colorless crystals after recrystallization from
CH2Cl2/petroleum ether, and were fully characterized by IR, 1H- and 13C-NMR, EI-MS,
and elemental analysis. Selected data are listed in the Table. In the case of 5l, the struc-
ture was additionally solved by single-crystal X-ray diffraction (Figure). All structures
were supported spectroscopically. For example, the IR spectrum of 5a revealed absorp-
tion bands at 1677 (C=O), 3145 (C6H5), and 3381 cmÀ1 (NH). The corresponding 1H-
NMR spectrum showed the 5-Me group at d(H) 2.96 (s), and the CH2 signals of the
cyclohexenyl ring appeared at d(H) 1.91, 2.88, and 3.31. The other signals resonated
at d(H) 7.26–7.65 (m, 5 arom. H), 0.88 (t, J=7.2 Hz, Me), 1.60 (q, J=7.2 Hz, CH2),
and 3.41–3.44 (m, NCH2). The mass spectrum of 5a showed the molecular ion peak
at m/z 404 as the base peak (100%). The structures of 5a and the other analogs were
further confirmed on the basis of elemental analysis.
We gratefully acknowledge financial support of this work by the National Key Project for Basic
Research (No. 2003CB114400) and the National Natural Science Foundation of China (No. 20372023).

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Helvetica Chimica Acta – Vol. 89 (2006)
Experimental Part
General. All solvents and materials were reagent-grade and purified as required. Melting point
(m.p.): WRS-1B Digital apparatus; uncorrected. IR Spectra: PE-983 IR spectrometer, as KBr pellets,
1
in cmÀ1. H- and 13C-NMR Spectra: Varian Mercury-400 spectrometer, in CDCl3 soln.; d in ppm rel. to
Me4Si, J in Hz. EI-MS: Finnigan Trace MS spectrometer; in m/z (rel. %). Elemental analyses: Vario
N
EL-III instrument.
Ethyl 4-Amino-5,6,7,8-tetrahydro-2-methyl[1]benzothieno[2,3-b]pyridine-3-carboxylate (2) [8]. 2-
Amino-4,5,6,7-tetrahydro[1]benzothiophene-3-carbonitrile (3; 1.78 g, 10 mmol) and SnCl4 (2.3 ml, 20
mmol) were added to a stirred soln. of ethyl acetoacetate (1.08 ml, 10 mmol) in anh. toluene (20 ml).
The mixture was stirred at r.t. for 1 h, and then heated at reflux for 5 h. The mixture was added to sat.
aq. Na2CO3 soln. (60 ml, pH 10), and the resulting suspension was extracted with AcOEt (3×50 ml).
The combined extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 2 in
1
64% yield. Colorless crystals. M.p. 137–1388. H-NMR: 1.42 (t, J=7.2, Me); 1.87–1.94 (m, CH2CH2);
2.73 (s, Me); 2.79–2.83 (m, CH2); 2.99–3.02 (m, CH2); 4.39 (q, J=7.2, CH2O); 6.60 (s, NH2).
Ethyl 5,6,7,8-Tetrahydro-2-methyl-4-[(triphenyl-l5-phosphanylidene)amino][1]benzothieno[2,3-b]-
A
N
AHCTREUNG
18–24 h at 08. Then, the soln. was concentrated, and the residue was recrystallized from EtOH to give
1
1 in 90.2% yield. M.p. 225–2268. H-NMR: 0.99 (t, J=7.2, Me); 1.40–1.64 (m, CH2CH2); 2.41 (s, Me);
2.50–2.54 (m, CH2); 2.65–2.69 (m, CH2); 3.38 (q, J=7.2, CH2O); 7.44–7.62 (m, 15 arom. H).
General Procedure for the Preparation of Carbodiimides 4. To a soln. of 1 (0.525 g, 1 mmol) in anh.
CH2Cl2 (10 ml) was added the appropriate aryl isocyanate (1.1 mmol) under N2 at r.t. The mixture was
left standing for 30–40 min. Then, the solvent was removed in vacuo, and Et2
A
added to precipitate Ph3P=O. Filtration and removal of the solvent gave the crude carbodiimides 4,
AHCTREUNG
which were used directly without further purification.
General Procedure for the Preparation of Compounds 5a–n. To a soln. of 4 in CH2Cl2 (10 ml) was
added the appropriate alkylamine (1.1 mmol), and the mixture was stirred for 30 min. The solvent was
removed, anh. EtOH (10 ml), containing several drops of a soln of EtONa in EtOH, was added, and
the mixture was stirred for 11–14 h at r.t. (Table). After solvent removal, the residue was recrystallized
from EtOH to afford the target compounds.
8,9,10,11-Tetrahydro-5-methyl-3-phenyl-2-(propylamino)[1]benzothieno[3’,2’:5,6]pyrido[4,3-d]pyri-
midin-4(3H)-one (5a). IR: 3381 (NÀH), 3145 (Ar), 2895 (CÀH), 1677 (C=O), 1558, 1510, 1401, 1146,
1
806. H-NMR : 0.88 (t, J=7.2, Me); 1.58–1.62 (m, CH2); 1.88–1.92 (m, 2 CH2); 2.88–3.31 (m, 2 CH2);
2.96 (s, MeÀC(5)); 3.41–3.43 (m, NCH2); 4.36 (s, NH); 7.26–7.65 (m, 5 arom. H). MS: 406 (21), 404
(100, M+), 363 (38), 349 (30), 335 (97), 259 (49), 230 (15), 216 (16), 189 (42), 173 (29), 80 (97). Anal.
calc. for C23H24N4OS: C 68.29, H 5.98, N 13.85; found: C 68.11, H 6.06, N 14.00.
8,9,10,11-Tetrahydro-5-methyl-2-[(1-methylethyl)amino]-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido[4,
G
3-d]pyrimidin-4(3H)-one (5b). IR: 3339 (NÀH), 3112 (Ar), 2964, 2929 (CÀH), 1672 (C=O), 1558, 1510,
1448, 1409, 1280, 1164, 1017, 691. 1H-NMR: 1.18 (d, J=6.8, 2 Me); 1.90–1.94 (m, 2 CH2); 2.89–3.29 (m, 2
CH2); 2.97 (s, MeÀC(5)); 4.06 (s, NH); 4.30–4.34 (m, NCH); 7.26–7.66 (m, 5 arom. H). 13C-NMR: 162.9;
162.6; 157.8; 152.6; 149.0; 134.4; 133.6; 130.7; 130.1; 129.9; 128.7; 124.7; 124.4; 41.8; 31.2; 27.2; 25.9; 22.9;
20.1; 13.7. MS: 406 (21), 404 (100, M+), 389 (22), 362 (81), 347 (51), 334 (20), 286 (69), 216 (29), 180 (29),
118 (40), 76 (61). Anal. calc. for C23H24N4OS: C 68.29, H 5.98, N 13.85; found: C 68.48, H 6.12, N 13.81.
2-(Butylamino)-8,9,10,11-tetrahydro-5-methyl-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido[4,3-d]pyri-
midin-4(3H)-one (5c). IR: 3415 (NÀH), 3231 (Ar), 1672 (C=O), 1557, 1517, 1450, 1155, 805. 1H-NMR:
0.92 (q, J=7.2, Me); 1.28–1.31 (m, CH2); 1.52–1.60 (m, CH2); 1.90–1.93 (m, 2 CH2); 2.87–3.32 (m, 2
CH2); 2.96 (s, MeÀC(5)); 3.44–3.48 (m, NCH2); 4.34 (s, NH); 7.25–7.65 (m, 5 arom. H). MS: 418
(100, M+), 403 (21), 363 (42), 350 (52), 318 (43), 260 (12), 189 (45), 173 (30), 81 (44), 76 (55). Anal.
calc. for C24H26N4OS: C 68.87, H 6.26, N 13.39; found: C 68.99, H 5.99, N 13.09.
8,9,10,11-Tetrahydro-5-methyl-2-[(1-methylpropyl)amino]-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido-
ACHTREUNG
1

Helvetica Chimica Acta – Vol. 89 (2006)
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2.89–3.30 (m, 2 CH2); 2.97 (s, MeÀC(5)); 1.94–1.98 (m, CH), 3.58–3.62 (m, NCH2); 4.43 (s, NH);
7.26–7.65 (m, 5 arom. H). MS: 418 (100, M+), 403 (21), 376 (20), 363 (36), 361 (42), 348 (13), 346
(13). Anal. calc. for C24H26N4OS: C 68.87, H 6.26, N 13.39; found: C 68.86, H 6.11, N 13.34.
2-[(1,1-Dimethylethyl)amino]-8,9,10,11-tetrahydro-5-methyl-3-phenyl[1]benzothieno[3’,2’:5,6]pyri-
A
1558, 1511, 1449, 1294, 1213, 955, 806. H-NMR: 1.42 (s, t-Bu); 1.92–1.95 (m, 2 CH2); 2.88–3.29 (m, 2
CH2); 2.99 (s, MeÀC(5)); 4.24 (s, NH); 7.26–7.65 (m, 5 arom. H). MS: 420 (23), 418 (96, M+), 365
(20), 361 (100), 347 (82), 344 (23), 332 (38), 214 (21), 186 (20), 118 (23), 76 (58). Anal. calc. for
C24H26N4OS: C 68.87, H 6.26, N 13.39; found: C 69.03, H 6.09, N 13.21.
2-[(Furan-2-ylmethyl)amino]-8,9,10,11-tetrahydro-5-methyl-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido-
[4,3-d]pyrimidin-4(3H)-one (5f). IR: 3137 (Ar), 2958, 2935 (CÀH), 1686 (C=O), 1558, 1509, 1449, 1399,
1302, 1166, 1072, 742. 1H-NMR: 1.90–1.94 (m, 2 CH2); 2.89–3.31 (m, 2 CH2); 2.98 (s, MeÀC(5)); 4.70 (s,
NH); 6.20 (s, C=CH); 6.30 (s, C=CH); 6.32 (s, C=CH); 7.26–7.63 (m, 5 arom. H). MS: 442 (100, M+), 414
(34), 385 (30), 361 (33), 344 (12), 96 (10), 95 (18), 92 (10), 80 (90), 76 (24). Anal. calc. for C25H22N4O2S: C
67.85, H 5.01, N 12.66; found: C 67.71, H 4.87, N 12.58.
2-[(2,2-Dimethylpropyl)amino]-8,9,10,11-tetrahydro-5-methyl-3-phenyl[1]benzothieno[3’,2’:5,6]py-
rido[4,3-d]pyrimidin-4(3H)-one (5g). IR: 3126 (Ar), 2959, 2930 (CÀH), 1687 (C=O), 1580, 1558, 1511,
1448, 1284, 1142, 852, 705. 1H- NMR: 0.73 (t, J=7.6, Me); 1.37 (s, 2 Me); 1.78 (q, J=7.6, CH2);
1.91–1.94 (m, 2 CH2); 2.89–3.28 (m, 2 CH2); 2.98 (s, MeÀC(5)); 4.17 (s, NH); 7.27–7.66 (m, 5 arom.
H). MS: 434 (28), 432 (68, M+), 362 (100), 361 (38), 347 (30), 334 (23). Anal. calc. for C25
H28N4OS: C
A
69.41, H 6.52, N 12.95; found: C 69.61, H 6.47, N 13.06.
2-(Diethylamino)-8,9,10,11-tetrahydro-5-methyl-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido[4,3-d]pyri-
midin-4(3H)-one (5h). IR: 3121 (Ar), 2976, 2924 (CÀH), 1686 (C=O), 1559, 1542, 1509, 1400, 1091, 1051,
1
880, 690. H-NMR: 0.88 (t, J=6.8, 2 Me); 1.90–1.94 (m, 2 CH2); 2.89–3.30 (m, 2 CH2); 2.97 (s, MeÀ
C(5)); 3.28 (q, J=6.8, 2 CH2); 7.27–7.53 (m, 5 arom. H). MS: 420 (21), 418 (100, M+), 390 (92), 346
(25), 314 (19), 313 (35), 287 (7). Anal. calc. for C24H26N4OS: C 68.87, H 6.26, N 13.39; found: C 69.04,
H 6.43, N 13.35.
8,9,10,11-Tetrahydro-5-methyl-3-phenyl-2-piperidin-1-yl[1]benzothieno[3’,2’:5,6]pyrido[4,3-d]pyri-
midin-4(3H)-one (5i). IR: 3193 (Ar), 2928, 2852 (CÀH), 1719 (C=O), 1586, 1542, 1495, 1419, 1243, 1187,
1053, 692. 1H-NMR: 1.30–1.34 (m, 2 CH2); 1.58–1.62 (m, CH2); 1.81–1.85 (m, 2 CH2); 2.80–3.30 (m, 2
CH2); 2.98 (s, MeÀC(5)); 4.26–4.29 (m, 2 CH2N); 6.96–7.27 (m, 5 arom. H). MS: 431 (24, [M+1]+), 430
(24, M+), 404 (100), 393 (11), 384 (25), 346 (25), 270 (28), 91 (19), 82 (16). Anal. calc. for C25H26N4OS: C
69.74, H 6.09, N 13.01; found: C 69.58, H 6.21, N 13.36.
2-(Dibutylamino)-8,9,10,11-tetrahydro-5-methyl-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido[4,3-d]pyri-
midin-4(3H)-one (5j). IR: 3059 (Ar), 2956, 2931, 2850 (CÀH), 1691 (C=O), 1590, 1551, 1470, 1419, 1231,
1052, 804. 1H-NMR: 0.85 (t, J=7.2, 2 Me); 1.14–1.15 (m, 2 CH2); 1.26–1.29 (m, 2 CH2); 1.90–1.94 (m, 2
CH2); 2.89–3.30 (m, 2 CH2); 3.00 (s, MeÀC(5)); 3.11–3.12 (m, 2 NCH2); 7.27–7.54 (m, 5 arom. H). MS:
476 (25), 475 (56, [M+1]+), 474 (100, M+), 418 (78), 375 (33), 346 (25). Anal. calc. for C28H34N4OS: C
70.85, H 7.22, N 11.80; found: C 70.66, H 7.05, N 11.61.
2-(Dipropylamino)-8,9,10,11-tetrahydro-5-methyl-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido[4,3-d]py-
rimidin-4(3H)-one (5k). IR: 3195 (Ar), 2960, 2930 (CÀH), 1717 (C=O), 1586, 1563, 1496, 1419, 1239,
1190, 1052, 695. 1H-NMR: 0.75 (d, J=7.2, 2 Me); 1.30–1.34 (m, 2 CH2); 1.91–1.95 (m, 2 CH2);
2.89–3.31 (m, CH2); 2.99 (s, MeÀC(5)); 3.09–3.13 (m, 2 NCH2); 7.26–7.54 (m, 5 arom. H). MS: 447
(21, [M+1]+), 446 (57, M+), 420 (100), 417 (15), 404 (16), 403 (66), 400 (15), 375 (38), 362 (11), 225
(67), 118 (34). Anal. calc. for C26H30N4OS: C 69.92, H 6.77, N 12.54; found: C 69.75, H 6.63, N 12.71.
3-(4-Chlorophenyl)-8,9,10,11-tetrahydro-5-methyl-2-(propylamino)[1]benzothieno[3’,2’:5,6]pyrido-
A
1296, 1156, 1088, 752. 1H-NMR: 0.91 (t, J=7.2, Me); 1.62 (q, J=7.2, CH2); 1.88–1.93 (m, 2 CH2);
2.85–3.38 (m, 2 CH2); 2.94 (s, MeÀC(5)); 3.44–3.45 (m, NCH2); 4.41 (s, NH); 7.27–7.60 (m, 4 arom.
H). 13C-NMR: 162.9; 162.0; 157.4; 152.7; 148.1; 134.4; 134.1; 131.8; 130.7; 129.7; 128.9; 124.7; 124.6;
41.8; 27.2; 26.9; 22.9; 22.7; 21.1; 19.0; 13.7. MS: 440 (35), 439 (32, [M+1]+), 438 (100, M+), 398 (14),
396 (17), 395 (24), 111 (12), 110 (15), 43 (22). Anal. calc. for C23H23ClN4OS: C 62.93, H 5.28, N 12.76;
found: C 63.20, H 5.23, N 12.55. X-Ray analysis: see the Figure.

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Helvetica Chimica Acta – Vol. 89 (2006)
3-(4-Chlorophenyl)-8,9,10,11-tetrahydro-5-methyl-2-[(1-methylethyl)amino][1]benzothieno[3’,2’:5,6]-
ACHTREUNG
1
1251, 1164, 810. H-NMR: 1.20 (d, J=6.8, 2 Me); 1.90–1.94 (m, 2 CH2); 2.87–3.28 (m, 2 CH2); 2.94 (s,
MeÀC(5)); 4.05–4.06 (m, NCH); 4.31 (s, NH); 7.27–7.61 (m, 4 arom. H). MS: 440 (24), 439 (27,
[M+1]+ ), 438 (100, M+), 398 (8), 396 (9), 395 (15), 380 (6), 43 (16). Anal. calc. for C23H23ClN4OS: C
62.93, H 5.28, N 12.76; found: C 62.91, H 5.32, N 12.88.
2-(Butylamino)-3-(4-chlorophenyl)-8,9,10,11-tetrahydro-5-methyl[1]benzothieno[3’,2’:5,6]pyrido[4,
U
3-d]pyrimidin-4(3H)-one (5n). IR: 3181 (Ar), 2932 (CÀH), 1682 (C=O), 1581, 1550, 1510, 1489, 1401,
1299, 1154, 1015, 804. 1H-NMR: 0.92 (t, J=7.6, Me); 1.32 (q, J=7.6, CH2); 1.55–1.57 (m, CH2);
1.90–1.95 (m, 2 CH2); 2.88–3.31 (m, 2 CH2); 2.96 (s, MeÀC(5)); 3.46 (m, NCH2); 4.34 (s, NH);
7.26–7.61 (m, 4 arom. H). MS: 454 (25), 452 (100, M+), 410 (13), 397 (11), 395 (22), 110 (13), 56 (18).
Anal. calc. for C24H25ClN4OS: C 63.63, H 5.56, N 12.37; found: C 63.79, H 5.39, N 12.30.
General Procedure for the Preparation of Compounds 5o–q. To a soln. of 4 (400 mg, 1 mmol) in
MeCN (15 ml) was added EtOH (or a phenol; 1.1 mmol) and a cat. amount of K2CO3. The mixture
was stirred for 14 h at 808. Then, the soln. was concentrated, and the residue was recrystallized from
MeCN to afford the target compounds.
2-Ethoxy-8,9,10,11-tetrahydro-5-methyl-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (5o). IR: 3120 (Ar), 2982, 2934 (CÀH), 1682 (C=O), 1605, 1589, 1560, 1511, 1492, 1265, 1172,
1099, 805. 1H-NMR: 1.32 (t, J=7.2, Me); 1.92–1.96 (m, 2 CH2); 2.90–3.32 (m, 2 CH2); 3.02 (s, MeÀC(5));
4.53 (q, J=7.2, CH2); 7.25–7.54 (m, 5 arom. H). MS: 392 (100, M+), 387 (10), 362 (91), 334 (5), 76 (9).
Anal. calc. for C22H21N3O2S: C 67.50, H 5.41, N 10.73; found: C 67.56, H 5.25, N 10.87.
8,9,10,11-Tetrahydro-5-methyl-2-phenoxy-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (5p). IR: 3011 (Ar), 1698 (C=O), 1613, 1560, 1398, 1257, 1205, 806. 1H-NMR: 1.56–1.80 (m, 2
CH2); 2.43–2.82 (m, 2 CH2); 3.06 (s, MeÀC(5)); 7.13–7.60 (m, 10 arom. H). 13C-NMR: 162.1; 157.6;
152.8; 149.1; 146.0; 135.6; 134.8; 134.4; 133.3; 132.5; 131.6; 130.0; 129.6; 128.2; 128.0; 125.0; 124.8;
26.1; 25.8; 25.5; 22.4; 22.2. MS: 440 (35), 439 (32, [M+1]+), 438 (100, M+), 398 (14), 396 (17), 395
(24), 111 (12), 110 (15), 43 (22). Anal. calc. for C
H 5.00, N 9.62.
ACHTREUNG
2-[(4-Chlorophenyl)oxy]-8,9,10,11-tetrahydro-5-methyl-3-phenyl[1]benzothieno[3’,2’:5,6]pyrido
ACHTREUNG
3-d]pyrimidin-4(3H)-one (5q). IR: 3099 (Ar), 1700 (C=O), 1613, 1559, 1400, 1258, 1205, 841. 1H-NMR:
1.60–1.84 (m, 2 CH2); 2.44–2.84 (m, 2 CH2); 3.04 (s, MeÀC(5)); 7.09–7.62 (m, 9 arom. H). MS: 475 (41,
[M+1]+), 474 (100, M+), 460 (11), 444 (12), 396 (10), 380 (14), 110 (19), 76 (8). Anal. calc. for
C
ACHTREUNG
ꢀ
clinic, space group P1, a=11.8884(6), b=13.3784(7), c=15.7982(8) Å, a=114.0540(10), b=98.9260(10),
g=101.3350(10)8; V=2169.42(19) Å3; Z=4; Dc =1.344g/cm3; S=1.026; m=0.295 mmÀ1; Mr =438.96;
Rfinal =0.0530, wR=0.1345. For a structural representation, see the Figure. The crystallographic data of
5l have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC-278140. Copies of the data can be obtained, free of charge, via the internet (http://
www.ccdc.cam.ac.uk/data_request/cif), by e-mail (data_request@ccdc.cam.ac.uk), or by fax (+44-1223-
336033).
REFERENCES
[1] G. W. Rewcastle, B. D. Palmer, A. M. Thompson, A. J. Bridges, J. Med. Chem. 1996, 39, 1823.
[2] J. B. Smail, B. D. Palmer, G. W. Rewcastle, J. Med. Chem. 1999, 42, 1803.
[3] P. Bhuyan, R. C. Boruah, J. S. Sandhu, J. Org. Chem. 1990, 55, 568.
[4] M. Kajino, K. Meguro, Heterocycles 1990, 31, 2153.
[5] R. S. Hosmane, B. B. Lim, M. F. Summers, N. S. Hosmane, J. Org. Chem. 1988, 53, 5309.
[6] C. Bonini, M. D. Auria, M. Funicello, G. Romaniello, Tetrahedron 2002, 58, 3507.
[7] M. W. Ding, S. J. Yang, J. Zhu, Synthesis 2004, 75.

Helvetica Chimica Acta – Vol. 89 (2006)
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[8] A. C. Veronese, R. Callegari, C. F. Morelli, Tetrahedron 1995, 51, 12277.
[9] M. W. Ding, S. Z. Xu, J. F. Zhao. J. Org. Chem. 2004, 69, 8366.
[10] H. Wamhoff, S. Herrmann, S. Stolbern, Tetrahedron 1993, 49, 581.
[11] C. K. Johnson, ‘ORTEP-II. Report ORNL-5138’, 1976.
Received January 4, 2006