An efficient synthesis of new pyrido[4′,3′:4,5]thieno[2,3-d]- pyrimidin-4(3H)-one derivatives

Article abstract of DOI:10.1002/jhet.5570450639

(Chemical Equation Presented) The carbodiimides 5, obtained from reactions of iminophosphorane 4 with aromatic isocyanates, reacted with amines, phenols or ROH to give 2-substituted 5,6,7,8-tetrahydropyrido[4′,3′:4,5] thieno[2,3-d]-pyrimidin-4(3H)-one 7 i

Full text of DOI:10.1002/jhet.5570450639

Nov-Dec 2008
1809
An Efficient Synthesis of New Pyrido[4',3':4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one Derivatives
Guo-Ping Zeng [a,b], Yang-Gen Hu [a] and Ming-Wu Ding* [a]
[a] Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal
University, Wuhan, 430079, P. R. China; [b] Department of Chemistry and Life Science, Hubei University of
Education, Wuhan, 430205, P. R. China
e-mail: ding5229@yahoo.com.cn
Received December 21, 2007
O
Ph
Ph
COOEt
COOEt
NH2
PPh3, C2Cl6
NEt3
CNCH2COOEt
S, Morpholine
Ph
N
N
H3C
H3C
N=PPh3
Ph
N
S
S
Ph
Ph
CH3
O
Ph
Ar
Ph
COOEt
N
Base
HY
ArNCO
N
N
H3C
Y
H3C
N
N=C=NAr
S
S
Ph
Ph
The carbodiimides 5, obtained from reactions of iminophosphorane 4 with aromatic isocyanates, reacted
with amines, phenols or ROH to give 2-substituted 5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one 7 in the presence of catalytic amount of sodium alkoxide or solid potassium
carbonate in satisfactory yields.
J. Heterocyclic Chem., 45, 1809 (2008).
Scheme I
INTRODUCTION
O
O
The derivatives of heterocycles containing pyrido-
thieno–pyrimidine system possess a broad spectrum of
biological activities. They proved to be significant
antipyretic [1], anti-inflammatory [2,3] and antiallergic
activities [4]. Also some of these compounds show good
5-HT1A agonistical [5] or phosphodiesterase PDE7B
inhibitive activities [6]. The chemistry of pyridothieno-
pyrimidinones have also received attention because their
starting materials, 2-amino-3-carboxythiophenes, can be
conveniently synthesized by Gewald reaction [7].
Synthetically useful approaches to pyridothieno-
pyrimidines starting from easily accessible 2-amino-3-
carboxythiophenes are therefore of great importance.
Recently we have become interested in the preparation of
N-heteroaryl iminophosphoranes because these species
are promising building blocks for the synthesis of
nitrogen heterocycles [8-11]. Herein we wish to report an
efficient synthesis of new 2-substituted 5,6,7,8-tetra-
hydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
derivatives via iminophosphorane 4.
CNCH2COOEt
S, Morpholine
Ph
CH3NH2
Ph
N
Ph
Ph
CH3
1
2
Ph
Ph
COOEt
COOEt
NH2
PPh3, C2Cl6
NEt3
N
N
H3C
H3C
N=PPh3
S
S
Ph
Ph
4
3
Iminophosphorane 4 reacted with an equimolecular
quantity of the aromatic isocyanates to give the carbo-
diimides 5, which were allowed to react with aliphatic
amines to provide guanidine intermediates 6 (Y = NR1R2).
Even in refluxing toluene, the intermediates 6 did not
cyclize. However, by treatment with sodium ethoxide in
ethanol at room temperature, the intermediates
underwent intramolecular heterocyclization to give the
expected 2-amino-5,6,7,8-tetrahydropyrido[4',3':4,5]-thieno-
6
[2,3-d]pyrimidin-4(3H)-ones
7 in satisfactory yields
RESULTS AND DISCUSSION
(Scheme II). The results are listed in Table I.
The direct reaction of carbodiimide 5 with phenols
did not produce 2-aryloxy 5,6,7,8-tetrahydropyrido-
The ethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]
pyridine-3-carboxylate 3, easily obtained by Gewald
method from piperidinone 2 [12], ethyl cyanoacetate and
sulfur in the presence of morpholine, was converted to
[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones
7
either.
However, when carried our in the presence of catalytic
amount of potassium carbonate, the reaction took place to
give 7 (Y = OAr) in good yields (Table I). The formation
iminophosphorane
4
by treatment with triphenyl
phosphine, hexachloroethane and triethylamine in dry
acetonitrile (Scheme I).

1810
G.-P. Zeng, Y.-G. Hu and M.-W. Ding
Vol 45
Table I
Physical and Analytical Data of Compounds 7
Compd
Ar
Y
Time
hours
Mp
(°C)
Yield
% [a]
Molecular
Formula
Analysis %
Calcd./Found
H
C
N
9.26
9.47
10.80
10.59
9.17
9.25
8.45
7a
7b
7c
7d
7e
7f
Ph
N(n-C5H11)2
1-pyrrolidinyl
-N(i-Bu)2
-N(c-C6H11)2
4-morpholinyl
-NEt2
8
8
8
6
6
8
7
8
6
8
8
6
8
8
5
6
6
5
6
6
180-181
299-300
268-270
282-283
294-296
268-269
174-175
234-235
295-296
269-271
> 300
75
95
92
78
90
91
84
87
94
90
86
88
86
85
82
80
95
80
88
85
C38H44N4OS
75.46
75.52
74.10
74.08
70.74
70.82
72.43
72.20
69.54
69.38
71.35
71.58
73.28
73.17
72.70
72.76
71.97
72.76
73.82
74.07
69.24
69.26
71.35
71.52
71.35
71.11
70.88
70.97
75.65
75.85
70.88
70.75
73.00
73.23
67.76
67.84
68.24
68.52
70.43
70.52
7.33
7.23
5.83
6.02
6.43
6.41
6.53
6.40
5.29
5.17
5.80
5.85
6.96
7.12
6.61
6.44
5.67
5.84
6.19
6.04
5.63
5.58
5.80
5.94
5.80
5.62
4.55
4.62
5.26
5.31
4.55
4.64
5.51
5.45
4.71
4.82
4.96
4.78
5.12
5.32
Ph
C32H30N4OS
4-ClC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
Ph
C36H39ClN4OS
C40H43ClN4OS
C32H29FN4O2S
C32H31FN4OS
C38H43FN4OS
C36H39FN4O
8.41
10.14
10.26
10.40
10.36
9.00
8.79
9.42
9.53
10.17
10.03
10.76
10.51
10.09
10.12
10.40
10.36
10.40
10.55
7.29
7.06
7.56
7.48
7.29
7.36
8.51
8.38
8.17
8.04
7.96
7.72
8.21
7g
7h
7i
N(n-C5H11)2
-N(i-Bu)2
1-piperidinyl
t-BuNH
C33H31FN4OS
C32H32N4OS
7j
7k
7l
4-ClC6H4
4-FC6H4
4-FC6H4
Ph
t-BuNH
C32H31ClN4OS
C32H31FN4OS
C32H31FN4OS
C34H26ClN3O2S
C35H29N3O2S
C34H26ClN3O2S
C30H27N3O2S
C29H24ClN3O2S
C30H26ClN3O2S
C30H26FN3O2S
n-BuNH
t-BuNH
228-229
295-296
279-280
272-273
282-284
248-250
161-162
197-199
257-258
7m
7n
7o
7p
7q
7r
7s
4-ClC6H4O
4-MeC6H4O
C6H5O
Ph
4-ClC6H4
Ph
EtO
4-ClC6H4
4-ClC6H4
4-FC6H4
MeO
EtO
7t
EtO
8.07
[a] Isolated yields based on iminophosphorane 4.
of 7 can be rationalized in terms of an initial nucleophilic
addition of phenoxides to the carbodiimides 5 to give the
intermediates 6 which cyclize to give 7. The direct
reaction of carbodiimide 5 with ROH gave a complex
mixture, however, when the reaction was carried out in
the presence of catalytic amount of RO-Na+, the reaction
took place smoothly and 2-alkoxy 5,6,7,8-tetrahydro
pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones 7 (Y =
OR) were obtained in satisfactory yields (Table I).
The structure of the synthesized compound 7 was
confirmed by their spectral data and elemental analyses.
For example the 1H NMR spectral data of 7a show signals
for –NCH2 at 2.86-2.94 ppm as multiplets, signals of
NCH3 at 1.98 ppm as singlet and signals of (CH2)3CH3 at
0.80-1.20 ppm as multiplets. The tetrahydropyridine ring's
Scheme II
Ph
N
Ph
COOEt
COOEt
ArNCO
HY
N
H3C
H3C
N=PPh3
N=C=NAr
S
S
Ph
Ph
4
5
O
Ph
Ph
Ar
COOEt
N
N
Base
N
NHAr
Y
N
H3C
H3C
Y
N
S
S
Ph
Ph
7
6
signals appeared at 4.43 ppm (8-CH) as singlet and 3.10-
3.65 ppm (5,6-CH) as multiplets. The phenyl signals

Nov-Dec 2008
Synthesis of New Pyrido[4',3':4,5]thieno [2,3-d]pyrimidin-4(3H)-one Derivatives
1811
solvent was removed under reduced pressure and Et2O/
petroleum ether (1:2, 20 mL) was added to precipitate
triphenylphosphine oxide. Removal of the solvent gave
carbodiimides 5, which were used directly without further
purification. To the solution of 5 in dichloromethane (10 mL)
was added aliphatic amine (2 mmol). After the reaction mixture
was left unstirred for 5-6 h, the solvent was removed and
anhydrous EtOH (10 mL) with several drops of EtONa in EtOH
was added. The mixture was stirred for 6-8 h at room
temperature. The solution was condensed and residue was
recrystallized from EtOH to give the expected cyclic compouds
7a-7m in good yields.
2-Di(n-pentyl)amino-7-methyl-3,6,8-triphenyl-5,6,7,8-tetra
hydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a).
1H NMR (CDCl3): ꢀ 0.80-1.20 (m, 18H), 1.98 (s, 3H), 2.86-2.94
(m, 4H), 3.10-3.65 (m, 3H), 4.43 (s, 1H), 7.22-7.53 (m, 15H); ir
(potassium bromide): 1680 (C=O), 1542, 1376, 1214 cm-1; uv:
ꢁ max 302 nm; MS: m/z (%) 604 (31, M+), 484 (42), 359 (100),
318 (32), 274 (52), 218 (10).
appeared at 7.22-7.53 ppm. The MS spectrum of 7a
shows molecule ion peak (M+) at m/z 604 with 31%
abundance.
In conclusion, we have developed an efficient synthesis
of 2-substituted 5,6,7,8-tetrahydropyrido[4',3':4,5]thieno-
[2,3-d]pyrimidin-4(3H)-ones via reaction of functional-
ized carbodiimides with various amine, phenols or
alcohols. Due to the easily accessible and versatile
starting material, this method has potential in the
synthesis of many biologically and pharmaceutically
active pyridothienopyrimidinone derivatives.
EXPERIMENTAL
Melting points were determined using a X-4 model apparatus
and are uncorrected. MS were measured on a Finnigan Trace
MS spectrometer. NMR spectra were recorded in CDCl3 on a
Varian Mercury Plus 400 (400 MHz) spectrometer and chemical
shifts (ꢀ) were given in ppm using (CH3)4Si as an internal
reference (ꢀ = 0). IR spectra were recorded on a PE-983 infrared
spectrometer as KBr pellets with absorption in cm-1. UV spectra
7-Methyl-2-(1-pyrrolidinyl)-3,6,8-triphenyl-5,6,7,8-tetra-
hydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7b).
1H NMR (CDCl3): ꢀ 1.62-1.67 (m, 4H), 1.97 (s, 3H), 2.96 (t, J =
6.4 Hz, 4H), 3.08-3.66 (m, 3H), 4.45 (s, 1H), 7.19-7.51 (m,
15H); ir (potassium bromide): 1684 (C=O), 1545, 1368, 1210
cm-1; uv: ꢁ max 302 nm; MS: m/z (%) 518 (11, M+), 484 (9),
374 (18), 359 (100), 318 (11), 274 (12).
were recorded on
a SCINCO UV S-3100 spectrometer.
Elementary analyses were taken on a Vario EL III elementary
analysis instrument.
Ethyl 2-amino-5,7-diphenyl-6-methyl-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine-3-carboxylate (3). To a stirred mixture
of 1.33 g (0.005 mole) of piperidinone (2) [12], 0.16 g (0.005
mole) of sulfur, 0.57 g (0.005 mole) of ethyl cyanoacetate in 20
mL of ethanol, was added 1.2 mL of morpholine. After the
mixture was stirred at 35 °C for 48 hours, the solid was collected
by filtration and recrystallized from ethanol to give 3 as light
yellow needles, 1.25 g (64%), mp 195-197°; 1H NMR (CDCl3): ꢀ
1.22 (t, J = 7.2 Hz, 3H), 1.89 (s, 3H), 2.98-3.57 (m, 3H), 4.20 (q,
J = 7.2 Hz, 3H), 4.25 (s, 1H), 5.88 (s, 2H), 7.25-7.47 (m, 10H);
MS: m/z (%) 392 (48, M+), 315 (50), 269 (30), 198 (18), 118
(100), 91 (30). Anal. Calcd. for C23H24N2O2S: C, 70.38; H, 6.16;
N, 7.14. Found: C, 70.15; H, 6.23; N, 7.35.
3-(4-Chlorophenyl)-2-di(i-butyl)amino-6,8-diphenyl-7-methyl-
5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-
one (7c). H NMR (CDCl3): ꢀ 0.74 (d, J = 6.4 Hz, 12H), 1.72-
1.79 (m, 2H), 1.97 (s, 3H), 2.72-1.84 (m, 4H), 3.11-3.64 (m,
3H), 4.45 (s, 1H), 7.17-7.53 (m, 14H); ir (potassium bromide):
1685 (C=O), 1544, 1378, 1214 cm-1; uv: ꢁ max 300 nm; MS:
m/z (%) 611 (13, M+), 534 (77), 490 (68), 389 (14), 207 (28),
118 (100).
1
3-(4-Chlorophenyl)-2-dicyclohexylamino-6,8-diphenyl-7-
methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]-
1
pyrimidin-4(3H)-one (7d). H NMR (CDCl3): ꢀ 1.00-1.67 (m,
20H), 1.97 (s, 3H), 2.93 (t, J = 11.2 Hz, 2H), 3.12-3.64 (m, 3H),
4.45 (s, 1H), 7.15-7.53 (m, 14H); ir (potassium bromide): 1688
(C=O), 1540, 1385, 1226 cm-1; uv: ꢁ max 300 nm; MS: m/z (%)
663 (99, M+), 586 (100), 543 (94), 460 (22), 377 (26), 118 (88).
6,8-Diphenyl-3-(4-fluorophenyl)-7-methyl-2-(4-morpho-
linyl)-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one (7e). 1H NMR (CDCl3): ꢀ 1.97 (s, 3H),
3.03 (t, J = 4.0 Hz, 4H), 3.11-3.66 (m, 7H), 4.47 (s, 1H), 7.13-
7.51 (m, 14H); 13C NMR (CDCl3): ꢀ 164.5, 162.7, 161.1, 159.3,
154.2, 143.9, 143.5, 134.2, 132.5, 130.4, 130.3, 129.4, 128.7,
128.4, 128.2, 128.0, 127.7, 127.2, 116.8, 115.9, 115.8, 69.3,
66.6, 65.9, 49.2, 41.3, 35.9; ir (potassium bromide): 1688
(C=O), 1528, 1444, 1220 cm-1; uv: ꢁ max 304 nm; MS: m/z (%)
552 (67, M+), 475 (100), 432 (68), 207 (20), 118 (54), 95 (14).
2-Diethylamino-6,8-diphenyl-3-(4-fluorophenyl)-7-methyl-
5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-
Ethyl 5,7-diphenyl-6-methyl-2-(triphenylphosphoranyli-
dene)amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-car-
boxylate (4). To a mixture of ethyl 2-amino-5,7-diphenyl-6-
methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylate
(3) (3.14 g, 8 mmol), PPh3 (3.14 g, 12 mmol) and C2Cl6 (2.84 g,
12 mmol) in dry CH3CN (40 mL), was added dropwise NEt3
(2.42 g, 24 mmol) at room temperature. The color of the reaction
mixture quickly turned yellow. After stirring for 4 h, the solvent
was removed under reduced pressure and the residue was
recrystallized from EtOH to give iminophosphorane 4 as light
yellow needles, 4.33
g
(83%), mp 218-219°; 1H NMR
(CDCl3): ꢀ 1.24 (t, J = 7.2 Hz, 3H), 1.85 (s, 3H), 3.02-3.54 (m,
3H), 4.16 (q, J = 7.2 Hz, 3H), 4.23 (s, 1H), 7.19-7.75 (m, 25H);
MS: m/z (%) 652 (48, M+), 606 (63), 487 (100), 436 (23), 316
(10), 274 (23). Anal. Calcd. for C41H37N2O2PS: C, 75.44; H,
5.71; N, 4.29. Found: C, 75.68; H, 5.58; N, 4.32.
General Preparation of 2-Amino-5,6,7,8-tetrahydro
pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones (7a-7m).
To a solution of iminophosphorane 4 (1.30 g, 2 mmol) in
anhydrous CH2Cl2 (10 mL) was added aromatic isocyanate (2
mmol) under nitrogen atmosphere at room temperature. After
the reaction mixture was left unstirred for 6-12 h at 0-5 °C, the
iminophosphorane 4 had disappeared (TLC monitored). The
1
4(3H)-one (7f). H NMR (CDCl3): ꢀ 0.80 (t, J = 7.2 Hz, 6H),
1.98 (s, 3H), 2.94-3.04 (m, 4H), 3.09-3.65 (m, 3H), 4.46 (s, 1H),
7.11-7.52 (m, 14H); 13C NMR (CDCl3): ꢀ 165.3, 162.8, 161.2,
159.9, 154.6, 144.0, 143.6, 133.4, 133.0, 131.3, 129.9, 129.4,
129.3, 129.0, 128.6, 127.9, 127.6, 116.7, 116.5, 115.8, 115.1,
114.9, 69.8, 68.7, 46.4, 45.1, 43.7, 13.1; ir (potassium bromide):
1686 (C=O), 1525, 1508, 1381, 1226 cm-1; uv: ꢁ max 304 nm;
MS: m/z (%) 538 (36, M+), 461 (57), 418 (42), 208 (8), 193 (23),
118 (100).

1812
G.-P. Zeng, Y.-G. Hu and M.-W. Ding
Vol 45
2-Dipentylamino-6,8-diphenyl-3-(4-fluorophenyl)-7-
(C=O), 1554, 1336, 1225 cm-1; uv: ꢁ max 301 nm; MS: m/z (%)
538 (5, M+), 461 (5), 419 (11), 118 (100), 91 (26), 57 (97).
General Preparation of 2-Aryloxy-5,6,7,8-tetrahydro
pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones (7n-7p).
To the solution of carbodiimides 5 prepared above in dry
acetonitrile (10 mL) was added substituted phenol (2 mmol) and
solid K2CO3 (0.014 g, 0.1 mmol). The mixture was stirred for 5-
8 h at room temperature and filtered. The filtrate was condensed
and the residual was recrystallized from EtOH to give 7n-7p in
good yields.
methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]-
1
pyrimidin-4(3H)-one (7g). H NMR (CDCl3): ꢀ 0.83 (t, J = 7.2
Hz, 6H), 1.00-1.22 (m, 12H), 1.97 (s, 3H), 2.86-2.97 (m, 4H), 3.12-
3.65 (m, 3H), 4.46 (s, 1H), 7.11-7.52 (m, 14H); 13C NMR (CDCl3):
ꢀ 165.4, 163.1, 161.5, 159.9, 154.7, 143.9, 143.6, 133.4, 132.8,
131.2, 129.8, 129.3, 129.1, 129.0, 128.5, 127.9, 127.6, 127.4,
126.9, 126.4, 116.6, 116.4, 115.6, 115.0, 114.8, 69.8, 68.7, 52.4,
51.1, 49.8, 29.1, 27.0, 22.3, 14.6; ir (potassium bromide): 1685
(C=O), 1526, 1384, 1234 cm-1; uv: ꢁ max 303 nm; MS: m/z (%)
623 (99, M++1), 546 (92), 503 (100), 345 (22), 208 (41), 118 (95).
2-Di(i-butyl)amino-6,8-diphenyl-3-(4-fluorophenyl)-7-
methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one (7h). 1H NMR (CDCl3): ꢀ 0.74 (d, J = 6.4
Hz, 12H), 1.72-1.77 (m, 2H), 1.98 (s, 3H), 2.74-2.82 (m, 4H),
3.10-3.64 (m, 3H), 4.46 (s, 1H), 7.12-7.53 (m, 14H); ir
(potassium bromide): 1686 (C=O), 1528, 1379, 1230 cm-1; uv:
ꢁ max 302 nm; MS: m/z (%) 594 (94, M+), 518 (100), 474 (68),
208 (13), 118 (62), 91 (10).
2-(4-Chlorophenoxy)-7-methyl-3,6,8-triphenyl-5,6,7,8-
tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
1
(7n). H NMR (CDCl3): ꢀ 1.97 (s, 3H), 3.17-3.67 (m, 3H), 4.46
(s, 1H), 6.98-7.53 (m, 19H); ir (potassium bromide): 1692
(C=O), 1556, 1486, 1258 cm-1; uv: ꢁ max 301 nm; MS: m/z (%)
575 (16, M+), 498 (43), 456 (100), 118 (96), 91 (27), 77 (70).
7-Methyl-2-(4-methylphenoxy)-3,6,8-triphenyl-5,6,7,8-tetra-
hydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7o).
1H NMR (CDCl3): ꢀ 1.97 (s, 3H), 2.31 (s, 3H), 3.18-3.67 (m,
3H), 4.46 (s, 1H), 6.90-7.50 (m, 19H); 13C NMR (CDCl3): ꢀ
163.3, 158.9, 152.7, 149.4, 143.8, 143.4, 135.6, 134.6, 129.8,
129.3, 128.9, 128.6, 128.4, 128.1, 127.7, 127.2, 121.0, 117.4,
69.2, 66.6, 49.3, 41.3, 20.8; ir (potassium bromide): 1694
(C=O), 1556, 1495, 1257 cm-1; uv: ꢁ max 300 nm; MS: m/z (%)
555 (99, M+), 479 (98), 435 (100), 315 (51), 118 (99), 91 (88).
3-(4-Chlorophenyl)-2-phenoxy-6,8-diphenyl-7-methyl-5,6,
7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-
6,8-Diphenyl-3-(4-fluorophenyl)-7-methyl-2-(1-piperidinyl)-
5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-
1
one (7i). H NMR (CDCl3): ꢀ 0.74 (d, J = 6.4 Hz, 12H), 1.72-1.77
(m, 2H), 1.98 (s, 3H), 2.74-2.82 (m, 4H), 3.10-3.64 (m, 3H), 4.46 (s,
1H), 7.12-7.53 (m, 14H); ir (potassium bromide): 1686 (C=O),
1524, 1382, 1225 cm-1; uv: ꢁ max 304 nm; MS: m/z (%) 550 (64,
M+), 473 (97), 430 (71), 205 (31), 149 (24), 118 (100).
2-(t-Butyl)amino-7-methyl-3,6,8-triphenyl-5,6,7,8-tetra-
hydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7j).
1H NMR (CDCl3): ꢀ 1.27 (s, 9H), 1.97 (s, 3H), 3.11-3.65 (m,
3H), 3.93 (s, 1H), 4.44 (s, 1H), 7.18-7.56 (m, 15H); 13C NMR
(CDCl3): ꢀ 166.7, 159.0, 149.3, 144.3, 143.8, 134.8, 130.4,
130.2, 129.6, 129.1, 128.8, 128.7, 128.6, 128.3, 128.2, 127.9,
127.8, 127.1, 113.7, 69.3, 66.8, 52.6, 41.4, 36.0, 28.8; ir
(potassium bromide): 3430 (NH), 1678 (C=O), 1553, 1335,
1211 cm-1; uv: ꢁ max 301 nm; MS: m/z (%) 520 (98, M+), 444
(97), 401 (100), 387 (44), 224 (36), 118 (99).
1
one (7p). H NMR (CDCl3): ꢀ 1.97 (s, 3H), 3.18-3.67 (m, 3H),
4.46 (s, 1H), 7.02-7.48 (m, 14H); 13C NMR (CDCl3): ꢀ 163.2,
158.6, 152.2, 151.4, 143.7, 143.3, 134.9, 133.1, 130.4, 129.6,
129.4, 129.2, 128.7, 128.5, 128.1, 127.8, 127.3, 126.1, 121.2,
117.4, 69.1, 66.6, 41.3, 35.6; ir (potassium bromide): 1692
(C=O), 1555, 1488, 1260 cm-1; uv: ꢁ max 302 nm; MS: m/z (%)
575 (17, M+), 500 (21), 455 (37), 117 (100), 91 (23), 76 (50).
General Preparation of 2-Alkoxy-5,6,7,8-tetrahydro pyrido-
[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones (7q-7t). To the
solution of carbodiimides 5 prepared above in ROH (10 mL) was
added several drops of RONa in ROH. The mixture was stirred for
5-6 h at room temperature. The solution was condensed and the
residual was recrystallized from EtOH to give 7q-7t.
2-(t-Butyl)amino-3-(4-chlorophenyl)-6,8-diphenyl-7-
methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one (7k). 1H NMR (CDCl3): ꢀ 1.27 (s, 9H),
1.97 (s, 3H), 3.14-3.65 (m, 3H), 3.87 (s, 1H), 4.44 (s, 1H), 7.13-
7.53 (m, 14H); ir (potassium bromide): 3433 (NH), 1680 (C=O),
1554, 1335, 1220 cm-1; uv: ꢁ max 300 nm; MS: m/z (%) 555
(27, M+), 477 (53), 434 (35), 378 (45), 118 (100), 91 (62).
2-(n-Butyl)amino-3-(4-fluorophenyl)-6,8-diphenyl-7-
methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]-
2-Ethoxy-7-methyl-3,6,8-triphenyl-5,6,7,8-tetrahydro-
pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7q). 1H
NMR (CDCl3): ꢀ 1.18 (t, J = 7.2 Hz, 3H), 1.98 (s, 3H), 3.13-3.67
(m, 3H), 4.33 (q, J = 7.2 Hz, 2H), 4.48 (s, 1H), 7.16-7.52 (m,
15H); MS: m/z (%) 493 (46, M+), 416 (100), 374 (67), 345 (38),
118 (74), 91 (27).
1
pyrimidin-4(3H)-one (7l). H NMR (CDCl3): ꢀ 0.85 (t, J = 7.2
Hz, 3H), 1.18-1.43 (m, 4H), 1.97 (s, 3H), 3.23-3.66 (m, 5H),
3.98 (t, J = 4.2 Hz, 1H), 4.45 (s, 1H), 7.20-7.52 (m, 14H); 13C
NMR (CDCl3): ꢀ 167.2, 164.2, 161.4, 158.8, 150.3, 144.1,
143.7, 130.8, 130.5, 130.2, 129.0, 128.6, 128.3, 128.2, 127.8,
127.7, 127.1, 117.7, 117.4, 113.6, 69.2, 66.7, 41.6, 41.3, 35.9,
31.1, 19.9, 13.7; ir (potassium bromide): 3438 (NH), 1683
(C=O), 1552, 1334, 1222 cm-1; uv: ꢁ max 300 nm; MS: m/z (%)
538 (51, M+), 461 (84), 418 (83), 118 (100), 91 (43), 77 (40).
2-(t-Butyl)amino-3-(4-fluorophenyl)-6,8-diphenyl-7-
methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]-
3-(4-Chlorophenyl)-6,8-diphenyl-2-methoxy-7-methyl-5,6,
7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-
one (7r). 1H NMR (CDCl3): ꢀ 1.97 (s, 3H), 3.12-3.67 (m, 3H), 3.86
(s, 3H), 4.48 (s, 1H), 7.11-7.51 (m, 14H); 13C NMR (CDCl3): ꢀ
163.8, 158.6, 153.2, 143.8, 143.4, 134.6, 133.8, 133.0, 129.6,
129.4, 129.3, 128.7, 128.4, 128.2, 128.0, 127.7, 127.2, 116.7, 69.2,
66.6, 56.0, 41.3, 35.6; ir (potassium bromide): 1695 (C=O), 1561,
1492, 1263 cm-1; uv: ꢁ max 304 nm; MS: m/z (%) 513 (41, M+),
436 (100), 393 (98), 153 (33), 118 (59), 91 (22).
3-(4-Chlorophenyl)-6,8-diphenyl-2-ethoxy-7-methyl-
5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-
1
pyrimidin-4(3H)-one (7m). H NMR (CDCl3): ꢀ 1.28 (s, 9H),
1
1.97 (s, 3H), 3.08-3.65 (m, 3H), 3.89 (s, 1H), 4.44 (s, 1H), 7.17-
7.53 (m, 14H); 13C NMR (CDCl3): ꢀ 166.6, 164.3, 161.6, 159.0,
149.1, 144.2, 143.7, 131.6, 130.5, 130.0, 129.3, 129.0, 128.6,
127.9, 127.6, 127.5, 127.1, 118.3, 116.7, 113.6, 69.8, 68.7, 52.7,
45.2, 40.9, 28.8; ir (potassium bromide): 3437 (NH), 1681
4(3H)-one (7s). H NMR (CDCl3): ꢀ 1.21 (t, J = 7.2 Hz, 3H),
1.97 (s, 3H), 3.13-3.66 (m, 3H), 4.32 (q, J = 7.2 Hz, 2H), 4.47 (s,
1H), 7.10-7.52 (m, 14H); ); 13C NMR (CDCl3): ꢀ 164.0, 158.8,
152.7, 143.9, 143.4, 134.5, 133.6, 133.2, 129.6, 129.3, 128.7,
128.4, 128.2, 128.0, 127.8, 127.2, 116.6, 69.2, 66.6, 65.2, 41.3,

Nov-Dec 2008
Synthesis of New Pyrido[4',3':4,5]thieno [2,3-d]pyrimidin-4(3H)-one Derivatives
1813
[2] Elslager, E. F.; Jacob, P. W.; Leslio, M. J. Heterocycl. Chem.
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[3] Leistner, S.; Wagner, G.; Guetscharo, M.; Glusa, E.
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[5] Steiner, G.; Schellhaas, K.; Szabo, L.; Behl, B.; Garcia-
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[8] Yuan, J. Z.; Fu, B. Q.; Ding, M. W.; Yang, G. F. Eur. J. Org.
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35.7, 14.0; ir (potassium bromide): 1691 (C=O), 1557, 1491,
1261 cm-1; uv: ꢀ max 300 nm; MS: m/z (%) 527 (9, M+), 450
(33), 408 (21), 171 (25), 153 (33), 118 (100).
6,8-Diphenyl-2-ethoxy-3-(4-fluorophenyl)-7-methyl-5,6,7,8-
tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
1
(7t). H NMR (CDCl3): ꢁ 1.19 (t, J = 7.2 Hz, 3H), 1.98 (s, 3H),
3.17-3.66 (m, 3H), 4.33 (q, J = 7.2 Hz, 2H), 4.48 (s, 1H), 7.13-
7.52 (m, 14H); ); ir (potassium bromide): 1698 (C=O), 1560,
1492, 1264 cm-1; uv: ꢀ max 300 nm; MS: m/z (%) 511 (50, M+),
434 (100), 393 (51), 363 (42), 118 (8), 91 (10).
Acknowledgement. We gratefully acknowledge financial
support of this work by the National Natural Science Foundation
of China (Project No. 20772041) and the Key Project of Chinese
Ministry of Education (No. 107082).
[10] Ding, M. W.; Xu, S. Z.; Zhao, J. F. J. Org. Chem. 2004, 69,
8366.
REFERENCES
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