Synthesis and structure of 2-substituted thieno[3′,2′:5,6] pyrido-[4,3-d]pyrimidin-4(3H)-one derivatives

Article abstract of DOI:10.1002/hlca.200790103

A series of new 2-substituted 3-(4-chlorophenyl)-5,8,9- trimethylthieno[3′,2′:5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones 8 were synthesized via an aza-Wittig reaction. Phosphoranylideneamino derivatives 6a or 6b reacted with 4-chlorophenyl isocyanate to give c

Full text of DOI:10.1002/hlca.200790103

Helvetica Chimica Acta – Vol. 90 (2007)
999
Synthesis and Structure of 2-Substituted Thieno[3’,2’:5,6]pyrido-
[4,3-d]pyrimidin-4(3H)-one Derivatives
by Jian-Chao Liu, Hong-Wu He*, and Ming-Wu Ding
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan, 430079, P. R. China
(phone: þ 86(27)67865406; e-mail: journal@mail.ccnu.edu.cn)
A series of new 2-substituted 3-(4-chlorophenyl)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyr-
imidin-4(3H)-ones 8 were synthesized via an aza-Wittig reaction. Phosphoranylideneamino derivatives
6a or 6b reacted with 4-chlorophenyl isocyanate to give carbodiimide derivatives 7a or 7b, respectively,
which were further treated with amines or phenols to give compounds 8 in the presence of a catalytic
amount of EtONa or K2CO3. The structure of 2-(4-chlorophenoxy)-3-(4-chlorophenyl)-5,8,9-trime-
thylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-one (8j) was comfirmed by X-ray analysis.
1. Introduction. – The derivatives of pyrido[4,3-d]pyrimidine have recently
attracted the interest of pharmaceutical companies. Investigations of this family of
compounds are stimulated by the fact that a number of publications have been
concerned with the chemistry and the tumour-cell-growing activity of similar
derivatives [1 – 5]. The 2-substituted 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-
one derivatives 2 were synthesized by Bernath and co-workers [6] from N-substituted 4-
oxopiperidin-3-carboxylic acid methyl esters 1. Compounds 2 underwent dehydrogen-
ation in xylene or in nitrobenzene in the presence of a Pd/C catalyst, furnishing 2-
substituted pyrido[4,3-d]pyrimidin-4(3H)-one derivatives 3. However, this method
required forcing conditions and long reaction time.
Recently, we have been interested in the synthesis of quinazolinones, pyrazolopyr-
imidinones, and thienopyrimidinones via aza-Wittig reaction of (phosphoranylidenea-
mino)carboxylic acid ethyl esters with aromatic isocyanates and subsequent reaction
ꢀ 2007 Verlag Helvetica Chimica Acta AG, Zürich

1000
Helvetica Chimica Acta – Vol. 90 (2007)
with various nucleophiles [7][8], and 2-substituted 3-aryl-8,9,10,11-tetrahydro-5-
methyl[1]benzothieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-one derivatives were re-
ported [9]. Here we wish to report a facile synthesis of 2-substituted thieno[3’,2’:5,6]-
pyrido[4,3-d]pyrimidin-4(3H)-one derivatives 8 from easily accessible (phosphoranyl-
ideneamino)carboxylates 6. The structures of 8 were confirmed by 1H- and 13C-NMR,
EI-MS, IR spectroscopy, elemental analyses, and the single-crystal X-ray-analysis of 8j.
2. Results and Discussions. – The 4-amino-2,3,6-trimethylthieno[2,3-b]pyridine-5-
carboxylates 5, easily obtained from 2-amino-4,5-dimethylthiophene-3-carbonitril (4)
and methyl or ethyl 3-oxobutanoate in the presence of SnCl4, were converted to 4-
(phosphoranylideneamino) derivatives 6 via reaction with triphenylphosphine, hexa-
chloroethane, and Et3N (Scheme 1).
Scheme 1
a) See Table for R1 and R2.
Phosphoranylideneamino derivative 6b reacted with 4-chlorophenyl isocyanate to
give carbodiimide derivative 7b, which was allowed to react with amines R1R2NH or
phenols Ar1OH to produce 2-substituted 3-(4-chlorophenyl)-5,8,9-trimethylthie-
no[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones 8. Analogously, phosphoranylidenea-
mino derivative 6a reacted with 4-chlorophenyl isocyanate via 7a to the target
compounds 8. The cyclizations of 7 with amines to 8a – h proceeded smoothly in CH2Cl2
and in the presence of catalytic amounts of NaOEt at room temperature and gave
satisfactory yields with both primary and secondary alkylamines (Scheme 1 and Table).
The cyclizations of 7 with phenols in MeCN in the presence of catalytic amounts of
K2CO3 at room temperature did not lead to 2-(aryloxy)-3-(4-chlorophenyl)-5,8,9-
trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones. However, the reaction
took place smoothly to give 8i – r in good yields at higher temperature (Scheme 2 and
Table), and this with both phenols substituted by electron-withdrawing groups and
phenols substituted by electron-releasing groups. The yields of 8 from 6a were a bit
higher than those from 6b (see Table). All the products 8 were purified by

Helvetica Chimica Acta – Vol. 90 (2007)
1001
Scheme 2
a) For Ar1, see Table.
Table. Formation and Physical Constants of Compounds 8
R1R2NH or Ar1OH
Crystal color M.p. [8] Reaction time Reaction temp. Yield Yield
[h]
[8]
[%]a) [%]b)
8a MeCH2CH2NH2
8b Me2CHNH2
8c Me(CH2)3NH2
8d MeCH2CH(Me)NH2 colorless
8e Me3CNH2
8f (MeCH2)2NH
8g (Me(CH2)3)2NH
8h (Me(CH2)2)2NH
colorless
colorless
colorless
251 – 252 10
25
25
25
25
25
20
20
9490
298 – 299
9
89
90
89
85
92
87
88
86
82
84
89
76
248 – 249 11
258 – 259 11
colorless
colorless
colorless
colorless
yellow
colorless
colorless
colorless
colorless
colorless
colorless
colorless
colorless
colorless
> 300
10
220 – 223 10
199 – 201
9
190 – 19411
284– 286 12
> 300 12
25
93
80
8i
4-MeꢀC6H4ꢀOH
70
70
70
70
80
80
80
80
80
80
91
95
9486
77
86
80
67
82
69
92
89
91
8j 4-ClꢀC6H4ꢀOH
8k PhOH
276 – 277 13
254– 258 13
280 – 281 12
270 – 273 13
298 – 299 12
264– 265 13
265 – 266 12
265 – 267 12
8l
4-NO2ꢀC6H4ꢀOH
70
78
80
57
66
50
79
8m 2,4-Cl2C6H3OH
8n 2-ClꢀC6H4ꢀOH
8o 4-BrꢀC6H4ꢀOH
8p 2,4-F2C6H3OH
8q 3-FꢀC6H4ꢀOH
8r 2-Cl(4-F)C6H3OH
a) Yields of 8 from 6a. b) Yields of 8 from 6b.
1
recrystallization from CH2Cl2 and EtOH and their structures elucidated by H- and
13C-NMR, IR, MS, and elementary analysis.
For example, the IR spectrum of 8a reveals a C¼O absorption band at 1672 cmꢀ1, and absorptions at
1
3361 and 3045 cmꢀ1 are due to NꢀH and aromatic CꢀH groups. The H-NMR spectra of 8a show the
signal of the Me group at the pyridine moiety at d 2.96 as a s and those of the Me groups at the thiophene
ring at d 2.48 and 2.70. The signal of the NH group appears at d 4.42, and the aromatic H-atoms absorb at
d 7.26 – 7.62 (m, 4 H). The 13C-NMR shows nineteen signals. The MS of 8a reveals the molecule ion peak
at m/z 412 with 100% abundance. The structure of 8a was also established on the basis of elemental-
analysis data.
The structure of 8j was determined by X-ray crystallography (Fig.).

1002
Helvetica Chimica Acta – Vol. 90 (2007)
Figure. X-Ray crystal structure of thieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-one 8j
We gratefully acknowledge financial support of this work by the National Key Project for Basic
Research and the National Natural Science Foundation of China (No. 2003CB114400 and Project No.
20372023 ).
Experimental Part
1. General. All of the solvents and materials were reagent grade and purified as required. Melting
points: WRS-1B digital apparatus; uncorrected. IR Spectra: PE-983 IR spectrometer; KBr pellets; in
cmꢀ1. 1H- and 13C-NMR Spectra: Varian-Mercury-400 spectrometer; CDCl3 solns.; d in ppm rel. to SiMe4,
J in Hz. MS: Finnigan-Trace-MS spectrometer. Elemental analyses: Vario-EL-III instrument.
2. 4-Amino-2,3,6-trimethylthieno[2,3-b]pyridine-5-carboxylic Acid Methyl and Ethyl Ester (5a and
5b, resp.). The 2-amino-4,5-dimethylthiophene-3-carbonitrile (4; 1.52 g, 10 mmol) and SnCl4 (2.3 ml,
20 mmol) were added to a stirred soln. of methyl 3-oxobutanoate (1.18 g, 10 mmol) in dry toluene
(20 ml). The mixture was stirred at r.t. for 0.5 h and then heated under reflux for 4h. Then the mixture
was added to a sat. aq. Na2CO3 soln. (60 ml; pH 10 – 11), the suspension extracted with AcOEt (3 ꢁ
50 ml), and the combined extract dried (Na2SO4) and concentrated: 1.21 g (48%) of 5a. Colorless
crystals. M.p. 178 – 1798. 1H-NMR (CDCl3, 400 MHz): 2.40 (s, Me); 2.51 (s, Me ); 2.69 (s, MeꢀC(6)); 3.91
(s, MeO); 6.68 (s, NH2). Anal. calc. for C12H14N2O2S (250.32): C 57.58, H 5.64, N 11.19; found: C 57.70, H
5.33, N 10.91.
Compound 5b was prepared according to [10][11] in 69% yield. Colorless crystals. M.p. 131 – 1328.
3. 2,3,6-Trimethyl-4-[(triphenylphosphoranylidene)amino]thieno[2,3-b]pyridine-5-carboxylic Acid
Methyl and Ethyl Ester (6a and 6b, resp.). To a soln. of 5a (1.00 g, 4mmol) in MeCN (15 ml) were
added Ph3P (1.30 g, 5 mmol) and C2Cl6 (1.20 g, 5 mmol). The mixture was treated with Et3N (5.0 ml) and
then stirred for 5 – 10 h at 08. After evaporation, the residue was recrystallized from EtOH: 1.95 g (95%)
1
of 5a. M.p. 174– 175. H-NMR (CDCl3, 400 MHz): 2.12 (s, Me); 2.35 (s, Me); 2.4 9 (s, MeꢀC(6)); 3.36 (s,

Helvetica Chimica Acta – Vol. 90 (2007)
1003
MeO); 7.42 – 7.62 (m, 18 arom. H). Anal. calc. for C30H27N2O2PS (510.60): C 70.57, H 5.33, N 5.49; found:
C 70.68, H 5.09, N 5.32.
Compound 6b was prepared according to [10][11] in 93% yield. Colorless crystals. M.p. 174– 175 8.
4. 4-{[(4-Chlorophenyl)carbonimidoyl]amino}thieno[2,3-b]pyridine-5-carboxylic Acid Methyl and
Ethyl Ester (7a and 7b, resp.). To a soln. of 6a (0.51 g, 1 mmol) in dry CH2Cl2 (10 ml), 4-chlorophenyl
isocyanate (1.1 mmol) was added under N2 at r.t. The mixture was left unstirred for 30 min, then the
solvent was evaporated, and Et2O/petroleum ether was added to precipitate Ph3PO. Removal of the
solvent gave 7a, which was used directly without further purification.
Following this procedure, 6b (0.53 g, 1 mmol) gave 7b.
5. Compounds 8a – h: General Procedure. To the soln. of 7a or 7b (1 mmol) in CH2Cl2 (10 ml), the
alkylamine (1.1 mmol) was added. The mixture was stirred for 30 min, the solvent was removed, and anh.
EtOH (10 ml) with several drops of EtONa in EtOH were added. The mixture was stirred for 9 – 11 h at
r.t., the soln. concentrated, and the residue recrystallized from EtOH: 8a – h.
3-(4-Chlorophenyl)-5,8,9-trimethyl-2-(propylamino)thieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-
one (8a): IR: 3361 (NꢀH), 3045 (arom. CꢀH), 2963, 2925, 2867 (CꢀH), 1672 (C¼O), 1512, 1490, 1449,
1403, 1170, 1091, 808. 1H-NMR: 0.90 (t, J ¼ 7.2, Me); 1.61 – 1.64( m, CH2); 2.48 (s, Me); 2.70 (s, Me); 2.96
(s, Me); 3.45 – 3.47 (m, CH2); 4.42 (s, NH); 7.26 – 7.62 (m, 4arom. H). 13C-NMR: 11.2; 13.6; 14.7; 22.5;
26.4; 43.8; 113.7; 119.5; 121.8; 125.1; 126.3; 128.1; 130.2; 132.8; 136.2; 151.2; 152.7; 157.7; 162.5. MS: 413
(31), 412 (100, Mþ), 370 (13), 369 (18), 42 (28). Anal. calc. for C21H21ClN4OS (412.94): C 61.09, H 5.09, N
13.58; found: C 60.77, H 5.00, N 13.34.
3-(4-Chlorophenyl)-2-(isopropylamino)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8b): IR: 3438 (NꢀH), 3135 (arom. CꢀH), 1674(C ¼O), 1560, 1511, 1490, 1401, 1085.
1H-NMR: 1.21 (d, J ¼ 6.8, Me); 1.25 (d, J ¼ 6.8, Me); 2.48 (s, Me); 2.69 (s, Me); 2.95 (s, Me); 4 .07 (s, Me);
4.36 – 4.39 (m, NH); 7.26 – 7.62 (m, 4 arom. H). MS: 413 (27), 412 (36, Mþ), 411 (100), 373 (14), 368 (93),
352 (28), 260 (56), 258 (58), 189 (24), 80 (16). Anal. calc. for C21H21ClN4OS (412.94): C 61.09, H 5.09, N
13.58; found: C 60.78, H 4.93, N 13.42.
2-(Butylamino)-3-(4-chlorophenyl)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-
one (8c): IR: 3446 (NꢀH), 3187 (arom. CꢀH), 2959, 2924(C ꢀH), 1684(C ¼O), 1552, 1509, 1490, 1450,
1161, 796. 1H-NMR: 0.9 (t, J ¼ 7.2, Me); 1.30 – 1.34( m, CH2); 1.56 – 1.59 (m, CH2); 3.47 – 3.50 (t, CH2);
2.48 (s, Me); 2.70 (s, Me); 2.96 (s, Me ); 4.39 (s, NH); 7.26 – 7.61 (m, 4 arom. H). MS: 427 (26), 426 (100,
Mþ), 411 (17), 370 (9), 369 (16). Anal. calc. for C22H23ClN4OS (426.96): C 61.89, H 5.43, N 13.12; found:
C 61.59, H 5.14, N 13.24.
2-[(sec-Butyl)amino]-3-(4-chlorophenyl)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8d): IR: 3366 (NꢀH), 3035 (arom. CꢀH), 2958, 2924(C ꢀH), 1667 (C¼O), 1557, 1511,
1491, 1449, 1402, 1091, 805. 1H-NMR : 0.89 (d, J ¼ 6.8, 2 Me); 1.95 – 1.99 (m, CH); 2.4 9 (s, Me); 2.71 (s,
Me); 2.97 (s, Me); 3.32 (t, J ¼ 6.8, CH2); 4.42 (s, NH); 7.26 – 7.67 (m, 4 arom. H). MS: 427 (45), 426 (29,
Mþ), 368 (100), 352 (18), 189 (15), 172 (13). Anal. calc. for C22H23ClN4OS (426.96): C 61.89, H 5.43, N
13.12; found: C 61.60, H 5.24, N 12.97.
2-[(tert-Butyl)amino]-3-(4-chlorophenyl)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8e): IR: 3434 (NꢀH), 3135 (arom. CꢀH), 2967, 2924(C ꢀH), 1673 (C¼O), 1526, 1509,
1487, 1440, 1290, 1211, 1088, 809. 1H-NMR: 1.44 (s, 3 Me); 2.49 (s, Me); 2.73 (s, Me); 2.96 (s, Me); 4.22 (s,
NH); 7.26 – 7.62 (m, 4 arom. H). MS: 427 (14), 426 (64, Mþ), 370 (100), 368 (86), 352 (16), 189 (10).
Anal. calc. for C22H23ClN4OS (426.96): C 61.89, H 5.43, N 13.12; found: C 62.06, H 5.25, N 13.26.
3-(4-Chlorophenyl)-2-(diethylamino)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-
one (8f): IR: 3135 (arom. CꢀH), 2982, 2929 (CꢀH), 1675 (C¼O), 1557, 1511, 1490, 1254, 1089, 795.
1H-NMR: 0.95 (t, J ¼ 6.8, 2 Me); 2.50 (s, Me); 2.69 (s, Me); 3.00 (s, Me); 3.27 (q, J ¼ 6.8, CH2); 7.26 – 7.51
(m, 4 arom. H ). MS: 427 (19), 426 (82, Mþ), 400 (22), 397 (100), 354 (24), 286 (22). Anal. calc. for
C22H23ClN4OS (426.96): C 61.89, H 5.43, N 13.12; found: C 62.19, H 5.39, N 13.09.
3-(4-Chlorophenyl)-2-(dibutylamino)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-
one (8g): IR: 3135 (arom. CꢀH), 2928, 2866 (CꢀH), 1687 (C¼O), 1558, 1510, 1490, 1459, 1402, 804.
1H-NMR: 0.86 (d, J ¼ 7.2, 2 Me); 1.16 – 1.19 (m, 2 CH2); 1.30 – 1.36 (m, 2 CH2); 2.49 (s, Me); 2.68 (s, Me);
2.98 (s, Me); 3.15 (t, J ¼ 6.8, 2 CH2); 7.26 – 7.49 (m, 4 arom. H). MS: 483 (34), 482 (100, Mþ), 456 (14), 425

1004
Helvetica Chimica Acta – Vol. 90 (2007)
(87), 384(15), 383 (62), 354(40), 272 (26), 188 (19), 110 (11). Anal. calc. for C 26H31ClN4OS (483.07): C
64.64, H 6.47, N 11.60; found: C 64.90, H 6.63, N 11.86.
3-(4-Chlorophenyl)-2-(dipropylamino)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8h): IR: 3125 (arom. CꢀH), 2962, 2929 (CꢀH), 1686 (C¼O), 1520, 1490, 1485, 1402, 1090,
796. 1H-NMR: 0.78 (t, J ¼ 7.2, 2 Me); 1.33 – 1.39 (m, 2 CH2); 2.49 (s, Me); 2.69 (s, Me); 2.97 (s, Me); 3.10 –
3.14( m, (CH2)2N); 7.26 – 7.51 (m, 4 arom. H). MS: 455 (16), 454 (79, Mþ), 425 (16), 413 (23), 411 (100),
353 (57), 300 (57), 258 (25), 212 (34), 76 (16). Anal. calc. for C24H27ClN4OS (455.02): C 63.35, H 5.98, N
12.31; found: C 63.08, H 5.73, N 12.07.
6. Compounds 8i – r: General Procedure. To the soln. of 7a or 7b (1 mmol) in MeCN (10 ml), the
corresponding phenol (1.1 mmol) and a catalytic amount of K2CO3 were added. The mixture was stirred
for 12 – 13 h at 70 – 808, the soln. concentrated, and the residue recrystallized from MeCN: 8i – r.
3-(4-Chlorophenyl)-5,8,9-trimethyl-2-(4-methylphenoxy)thieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8i): IR: 3140 (arom. CꢀH), 2924(C ꢀH), 1699 (C¼O), 1504, 1490, 1405, 1316, 1198, 840.
1H-NMR : 2.01 (s, Me); 2.38 (s, Me); 2.39 (s, Me); 3.03 (s, Me); 7.00 – 7.57 (m, 8 arom. H). MS: 464 (30),
463 (33), 462 (100, Mþ), 356 (32), 354(93), 308 (41), 188 (64), 172 (21), 154(12), 106 (28), 76 (85).
Anal. calc. for C25H20ClN3O2S (461.96): C 65.00, H 4.36, N 9.10; found: C 65.25, H 4.16, N 8.96.
2-(4-Chlorophenoxy)-3-(4-chlorophenyl)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8j): IR: 3144 (arom. CꢀH), 1699 (C¼O), 1561, 1511, 1488, 1404, 1317, 1089, 845. 1H-NMR:
2.03 (s, Me ); 2.4 0 (s, Me); 3.02 (s, Me); 7.09 – 7.58 (m, 8 arom. H). MS: 483 (37), 482 (52), 481 (100, Mþ),
354(9), 98 (8), 38 (17). Anal. calc. for C 24H17Cl2N3O2S (482.38): C 59.76, H 3.55, N 8.71; found: C 60.01,
H 3.66, N 8.52.
3-(4-Chlorophenyl)-5,8,9-trimethyl-2-phenoxythieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-4(3H)-one
(8k): IR: 3140 (atom. CꢀH), 2934(C ꢀH), 1693 (C¼O), 1562, 1515, 1491, 1401, 1264, 1091, 806.
1H-NMR: 1.97 (s, Me); 2.39 (s, Me); 3.06 (s, Me); 7.13 – 7.58 (m, 9 arom. H). MS: 449 (29), 448 (29), 447
(100, Mþ), 356 (21), 355 (14), 354 (78), 76 (13), 64 (16). Anal. calc. for C24H18ClN3O2S (447.94): C 64.35,
H 4.05, N 9.38; found: C 64.30, H 3.75, N 9.63.
3-(4-Chlorophenyl)-5,8,9-trimethyl-2-(4-nitrophenoxy)thieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8l): IR: 3114(arom. C ꢀH), 1700 (C¼O), 1560, 1512, 1490, 1399, 1261, 1091, 862. 1H-NMR:
1.99 (s, Me); 2.40 (s, Me); 3.03 (s, Me); 7.37 – 8.35 (m, 8 arom. H). MS: 493 (19), 492 (41, Mþ), 445 (13),
372 (18), 370 (42), 369 (30), 292 (34), 214 (23), 76 (34), 62 (100). Anal. calc. for C24H17ClN4O4S (492.93):
C 58.48, H 3.48, N 11.37; found: C 58.72, H 3.67, N 11.60.
3-(4-Chlorophenyl)-2-(2,4-dichlorophenoxy)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8m): IR: 3120 (arom. CꢀH), 2919 (CꢀH), 1700 (C¼O), 1562, 1489, 1402, 1251, 1089, 804.
1H-NMR: 1.96 (s, Me); 2.41 (s, Me); 3.04( s, Me); 7.17 – 7.59 (m, 7 arom. H). MS: 519 (47), 518 (27), 517
(100, Mþ), 516 (24), 515 (98), 160 (46), 135 (21), 111 (17), 74 (18). Anal. calc. for C24H16Cl3N3O2S
(516.83): C 55.77, H 3.12, N 8.13; found: C 55.71, H 2.98, N 7.97.
2-(2-Chlorophenoxy)-3-(4-chlorophenyl)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8n): IR: 3137 (arom. CꢀH), 2935 (CꢀH), 1689 (C¼O), 1561, 1490, 1400, 1264, 1222, 1090,
804. 1H-NMR: 1.89 (s, Me); 2.39 (s, Me); 3.06 (s, Me); 7.22 – 7.59 (m, 7 arom. H). MS: 483 (65), 482 (24),
481 (100, Mþ), 354(18), 126 (15), 110 (32), 98 (41). Anal. calc. for C 24H17Cl2N3O2S (482.38): C 59.76, H
3.55, N 8.71; found: C 59.54, H 3.33, N 8.90.
2-(4-Bromophenoxy)-3-(4-chlorophenyl)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8o): IR: 3136 (arom. CꢀH), 2925 (CꢀH), 1699 (C¼O), 1561, 1486, 1402, 1264, 1205, 1090,
843. 1H-NMR: 2.04( s, Me); 2.4 2 (s, Me); 3.04( s, Me); 7.04– 7.58 ( m, 8 arom. H). 13C-NMR: 13.6; 13.7;
26.3; 119.3; 122.4; 123.9; 125.7; 126.5; 128.0; 129.3; 129.7; 132.3; 132.4; 134.4; 137.7; 149.5; 150.6; 153.9;
157.6; 162.6. MS: 529 (30), 528 (24), 527 (100, Mþ), 526 (23), 525 (83), 354(11). Anal. calc. for
C24H17BrClN3O2S (526.83): C 54.72, H 3.25, N 7.98; found: C 54.53, H 3.37, N 8.23.
3-(4-Chlorophenyl)-2-(2,4-difluorophenoxy)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8p): IR: 3124(arom. C ꢀH), 2924(C ꢀH), 1704(C ¼O), 1562, 1507, 1401, 1371, 1189, 962,
830. 1H-NMR: 2.01 (s, Me); 2.4 2 (s, Me); 3.06 (s, Me); 6.93 – 7.59 (m, 7 arom. H). MS: 484 (18), 483 (81,
Mþ), 356 (26), 354(100), 189 (28), 186 (12), 159 (18), 110 (16), 100 (19). Anal. calc. for
C24H16F2ClN3O2S (483.92): C 59.57, H 3.33, N 8.68; found: C 59.52, H 3.57, N 8.59.

Helvetica Chimica Acta – Vol. 90 (2007)
1005
3-(4-Chlorophenyl)-2-(3-fluorophenoxy)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
4(3H)-one (8q): IR: 3125 (arom. CꢀH), 2933 (CꢀH), 1698 (C¼O), 1562, 1490, 1399, 1264, 1091, 866.
1H-NMR: 2.04( s, Me); 2.4 2 (s, Me); 3.07 (s, Me); 6.94– 7.57 ( m, 8 arom. H). MS: 467 (36), 466 (44), 465
(100, Mþ), 354(74), 189 (15), 110 (15), 94(17), 82 (19). Anal. calc. for C 24H17FClN3O2S (465.93): C 61.87,
H 3.68, N 9.02; found: C 62.10, H 3.61, N 9.20.
2-(2-Chloro-4-fluorophenoxy)-3-(4-chlorophenyl)-5,8,9-trimethylthieno[3’,2’:5,6]pyrido[4,3-d]pyri-
midin-4(3H)-one (8r): IR: 3128 (arom. CꢀH), 2927 (CꢀH), 1700 (C¼O), 1559, 1490, 1399, 1371, 1267,
1
1188, 1090, 861. H-NMR: 1.96 (s, Me); 2.4 1 (s, Me); 3.06 (s, Me); 7.07 – 7.59 (m, 7 arom. H). MS: 502
(13), 501 (48), 500 (26), 499 (100, Mþ), 356 (29), 354(100), 188 (37), 172 (12), 116 (21). Anal. calc. for
C24H16FCl2N3O2S (500.37): C 57.61, H 3.22, N 8.40; found: C 57.57, H 3.26, N 8.52.
X-Ray Crystallographic Analysis of Compound 8j. The structure of 8j, which was recrystallized from
EtOH, was determined by single-crystal X-ray diffraction analysis. The crystal is of monoclinic space
group P2(1)/n, with a ¼ 11.186(2) Š, b ¼ 10.335(2) Š, c ¼ 19.517(3) Š, b ¼ 101.377(3)8, V ¼ 2212.0(6)
Š3, Z ¼ 4, Dc ¼ 1.448 g/cm3, S ¼ 1.097, m ¼ 0.295 mmꢀ1, Mr 482.37, final R ¼ 0.0498, and wR ¼ 0.1364.
The Figure shows the molecular structure of 8j. CCDC-264861 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request.cif from the Camdridge Crystallographic Data Center.
REFERENCES
[1] A. Rosowsky, H. Bader, R. G. Moran, J. H. Freisheim, Heterocycl. Chem. 1989, 26, 509.
[2] E. C. Taylor, P. S. Ray, J. Org. Chem. 1988, 53, 35.
[3] A. Rosowsky, R. A. Forsch, J. H. Freisheim, R. G. Moran, J. Med. Chem. 1989, 32, 517.
[4] G. W. Rewcastle, B. D. Palmer, A. M. Thompson, A. G. Bridges, J. Med. Chem. 1996, 39, 1823.
[5] J. B. Smail, B. D. Palmer, G. W. Rewcastle, J. Med. Chem. 1999, 42, 1803.
[6] I. Huber, F. Fulop, J. Lazar, G. Bernath, G. Toth, J. Chem. Soc., Perkin Trans. 1 1992, 157.
[7] M. W. Ding, S. Z. Xu, J. F. Zhao, J. Org. Chem. 2004, 69, 8366.
[8] M. W. Ding, Y. F. Chen, N. Y. Huang, Eur. J. Org. Chem. 2004, 3872.
[9] J. C. Liu, H. W. He, Q. Y. Ren, M. W. Ding, Helv. Chim. Acta 2006, 89, 1337.
[10] A. C. Veronese, R. Callegari, C. F. Morelli, Tetrahedron 1995, 51, 12277.
[11] H. B. Zhou, Z. P. Cui, J. C. Liu, H. W. He, M. W. Ding, J. Central Normal Univ. (Nat. Sci.) 2005, 39,
343.
Received January 4, 2007