6202
M.E. Chizhova et al. / Tetrahedron 71 (2015) 6196e6203
(6-C), 114.4 (4a-C), 53.1 (CO2CH3), 13.6 (SCH3); HRMS (ESI): MHþ,
4.14. Methyl 4-(1-amino-3-methoxy-3-oxo-1-phenylprop-1-
en-2-yl)-2-(methylsulfanyl)-7-phenylpyrido[2,3-d]pyrimi-
dine-6-carboxylate (7)
found 373.0610. [C16H13N4O5S]þ requires 373.0601.
4.10. Methyl 7-(3,4-dimethoxyphenyl)-2-(methylsulfanyl)-4-
oxo-3,4-dihydropyrido[2,3-d]pyrimidine-6-carboxylate (6i)
To a solution of aldehyde 1 (500 mg, 2.25 mmol) and enamine
4b (878 mg, 4.93 mmol) in DMF (3 mL) a few drops of satd ethereal
HCl were added followed by stirring at room temperature for 2 h
(controlled by TLC). Solvent was removed in vacuo (50 ꢀS/5 Torr),
the residue was treated with water (10 mL) and aqueous phase was
separated. To the oily viscous residue was added DMSO (5 mL) and
mixture was heated at 80 ꢀS for 10 min. After cooling to room
temperature formed crystals were filtered, washed with water and
dried in air to give the mixture of compounds 6b and 7 (515 mg,
w1:2.5). Compound 7 was isolated by column chromatography on
silica (EtOAc-Hexane 1:1, Rfw0.5) to yield 214 mg (20%) as yellow
powder, mp 204e205 ꢀC; nmax(KBr) 3400e3200, 1727, 1688, 1595,
1549, 1514, 1438, 1332, 1264, 1218, 1133, 1019, 773, 700; dH
(400 MHz, DMSO-d6) 9.08 (1H, br.s, NH), 8.67 (1H, s, 5-H), 8.32 (1H,
Colorless powder, mp 278e280 ꢀC (DMF); nmax(KBr) 3071e2908,
1731, 1655, 1566, 1412, 1266, 1121, 1100, 1021, 871,; dH (400 MHz,
DMSO-d6, 60 ꢀC) 13.02 (1H, br.s, NH), 8.62 (1H, s, 5-H), 7.20 (1H, d,
20-H, J 2.0), 7.16 (1H, dd, 60-H, J 8.3, 2.0), 7.08 (1H, d, 50-H, J 8.3), 3.84
(3H, s, 40-OCH3), 3.81 (3H, s, 30-OCH3), 3.74 (3H, s, CO2CH3), 2.64
(3H, s, SCH3); dC (100.6 MHz, DMSO-d6, 60 ꢀC) 167.6 (CO2CH3), 163.8
(2-S), 162.9 (7-C), 161.5 (4-C), 158.6 (8a-C), 151.0 (40-C), 149.0 (30-C),
138.4 (5-C), 131.9 (10-C), 124.4 (6-C), 122.5 (60-C), 113.3 (20-C), 113.1
(4a-C), 112.2 (50-C), 56.4 (40-OCH3), 56.3 (30-OCH3), 52.9 (CO2CH3),
13.5 (SCH3); HRMS (ESI): MHþ, found 388.0967. [C18H18N3O5S]þ
requires 388.0962.
br.s, NH), 7.66e7.47 (5H, m, 7-(Ph)), 7.29e7.06 (5H, m,
b-(Ph)), 3.74
4.11. Ethyl 7-(2-chlorophenyl)-2-(methylsulfanyl)-4-oxo-3,4-
dihydropyrido[2,3-d]pyrimidine-6-carboxylate (6j)
(3H, s, 6-(CO2CH3)), 3.54 (3H, s, -(CO2CH3)), 2.40 (3H, s, SCH3); dC
a
(100.6 MHz, DMSO-d6, 60 ꢀC) 173.8, 170.3, 168.4, 167.2, 166.0, 164.0,
158.2, 140.3, 139.4, 137.1, 130.0, 129.8, 129.1, 128.6, 128.4, 125.0,
116.0, 92.3, 79.6, 53.0, 51.0, 14.1 (SCH3); HRMS (ESI): MHþ, found
487.1444. [C26H23N4O4S]þ requires 487.1435.
Yellow powder, mp 214e215 ꢀC (MeCN); nmax(KBr) 3163e2800,
1718, 1685, 1601, 1567, 1400, 1266, 1249, 1107, 1056, 975, 814, 736;
dH (400 MHz, DMSO-d6, 60 ꢀC) 13.04 (1H, br s, NH), 8.85 (1H, s, 5-H),
7.53e7.44 (4H, m, 2-Cl-C6H4), 4.12 (2H, q, OCH2CH3, J 7.1), 2.63 (3H,
s, SCH3),1.04 (3H, t, OCH2CH3, J 7.1); dC (100.6 MHz, DMSO-d6, 60 ꢀC)
164.73 (2-C) 164.65 (CO2CH2CH3),162.7 (7-C),161.5 (4-C),159.2 (8a-
C), 139.8 (20-C), 138.8 (5-C), 131.5 (10-C), 130.6 (60-C), 130.4 (40-C),
129.1 (50-C), 127.3 (30-C), 124.3 (6-C), 114.4 (4a-C), 61.6 (CH2CH3),
13.9 (CH2CH3), 13.5 (SCH3); HRMS (ESI): MHþ, found 376.0523.
[C17H1535ClN3O3S]þ requires 376.0517.
4.15. 2-(Methylsulfanyl)-4-oxo-7-phenyl-3,4-dihydropyrido
[2,3-d]pyrimidine-6-carboxylic acid (8)
A mixture of compound 6b (523 mg, 1.6 mmol) and aq KOH
(263 mg, 4.7 mmol in 10 mL of water) was stirred at room tem-
perature for 2 h. The solution was acidified with 3N citric acid to
pHw6. The precipitate was filtered, washed with water and dried in
air to give the titled compound (71%) as colourless powder, mp
296e297 ꢀC (DMF; decomp.); nmax(KBr) 3575e2600, 1735, 1678,
1600, 1568, 1403, 1266, 1124, 978, 815; dH (400 MHz, DMSO-d6,
60 ꢀC) 12.76 (2H, br s, NH, COOH), 8.68 (1H, s, 5-H), 7.64e7.59 (2H,
m, o-H(Ph)), 7.51e7.46 (3H, m, m,p-H(Ph)), 2.65 (3H, s, SCH3); dC
(100.6 MHz, DMSO-d6, 60 ꢀC) 168.0 (7-C), 163.74 (CO2H), 163.69 (2-
C), 161.6 (8a-C), 158.4 (4-C), 139.9 (ipso-Ph), 138.3 (5-C), 129.6 (p-
Ph), 129.2 (o-Ph), 128.3 (m-Ph), 125.7 (6-C), 113.43 (4a-C),13.5
(SCH3); HRMS (ESI): (MꢂH)ꢂ, found 312.0434. [C15H10N3O3S]þ re-
quires 312.0448.
4.12. Ethyl 2-(methylsulfanyl)-4-oxo-7-(thiophen-2-yl)-3,4-
dihydropyrido[2,3-d]pyrimidine-6-carboxylate (6k)
Colorless powder, mp 280e282 ꢀC (DMF; decomp.); nmax(KBr)
3063e2704, 1726, 1669, 1568, 1419, 1392, 1278, 1252, 1117, 851, 716;
dH (400 MHz, DMSO-d6, 60 ꢀC) 12.84 (1H, br.s, NH), 8.55 (1H, s, 5-H),
7.82 (1H, dd, 50-H, J 5.0, 1.0), 7.54 (1H, dd, 30-H, J 3.8, 1.0), 7.20 (1H,
dd, 40-H, J 3.8, 5.0), 4.37 (2H, q, CH2CH3, J 7.1), 2.66 (3H, s, SCH3), 1.30
(3H, t, CH2CH3, J 7.1); dC (100.6 MHz, DMSO-d6, 60 ꢀC) 167.2
(CO2CH2CH3), 164.1 (2-C),161.3 (4-C), 158.4 (8a-C),154.9 (7-C), 141.9
(20-C), 138.2 (5-C), 131.6 (50-C), 130.1 (30-C), 128.7 (40-C), 123.5 (4a-
C), 113.1 (6-C), 62.3 (CH2CH3), 14.2 (CH2CH3), 13.6 (SCH3); HRMS
(ESI): MHþ, found 348.0468. [C15H14N3O3S2]þ requires 348.0471.
4.16. 7-Phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (9)
A mixture of acid 8 (169 mg, 0.54 mmol), Cu2O (77 mg,
0.54 mmol) and N-methylpyrrolidone (1.5 mL) was heated at
205 ꢀS for 12 h. The mixture was concentrated (85 ꢀS/5 Torr) and
the residue was treated with EtOAc (5 mL) and passed through SiO2,
washing out with EtOAc (Rfw0.5). After evaporation of solvent the
residue was treated with ether (3 mL), ice-cooled and filtered to
give the titled compound (23 mg, 18%) ofw90% purity, beige pow-
der, mp 278e280 ꢀC (decomp.); nmax(KBr) 3433, 3178, 3056, 2817,
1709, 1675, 1611, 1575, 1411, 1276; dH (400 MHz, DMSO-d6) 11.53
(1H, br s, 1-NH), 11.28 (1H, br.s, 3-NH), 8.32 (1H, d, 5-H, J 8.1),
8.17e8.14 (2H, m, o-Ph), 7.81 (1H, d, 6-H, J 8.1), 7.58e7.53 (3H, m,
m-, p-Ph); dC (100.6 MHz, DMSO-d6, 60 ꢀC) 162.6 (8a-C), 161.2 (7-C),
152.9 (4-C), 150.9 (2-C), 137.9 (5-C), 137.7 (ipso-Ph), 130.9 (p-Ph),
129.3 (m-Ph), 127.8 (o-Ph), 115.8 (6-C), 109.1 (4a-C); HRMS (ESI):
MHþ, found 240.0769. [C13H10N3O2]þ requires 240.0768.
4.13. Methyl 4-chloro-2-(methylsulfanyl)-7-phenylpyrido[2,3-
d]pyrimidine-6-carboxylate (5b)
A mixture of compound 6b (300 mg, 0.92 mmol), phosphorus
oxychloride (310 mg, 2.02 mmol), dry toluene (20 mL) and dry 1,4-
dioxane (4 mL) was stirred at reflux temperature for 3 h (controlled
by TLC). After cooling to room temperature it was diluted with
dichloromethane (25 mL) and passed through a short pad of silica.
After evaporation of solvents the residue was thoroughly washed
with warm hexane and dried in vacuo to give the title compound 5b
(187 mg, 59%) as a pale yellow powder; mp 137e139 ꢀC, nmax(KBr)
1737, 1599, 1565, 1510, 1429, 1351, 1250, 1140, 1102, 1041, 1024; dH
(400 MHz, CDCl3) 8.90 (1H, s, 5-H), 7.71e7.69 (2H, m, o-H(Ph)),
7.58e7.44 (3H, m, m,p-H(Ph)), 3.79 (3H, s, CO2CH3), 2.77 (3H, s,
SCH3); dC (100.6 MHz, CDCl3) 175.1 (2-C); 166.88, 166.82 (7-C,
CO2CH3); 162.4 (4-C),158.8 (8a-C),138.6 (5-C, ipso-Ph; overlapped);
130.2 (p-Ph), 128.9 (o-Ph), 128.4 (m-Ph); 126.6 (6-C), 114.1 (4a-C),
52.9 (CO2CH3), 14.9 (SCH3); HRMS (ESI): MHþ, found 346.0414.
[C16H13ClN3O2S]þ requires 346.0412.
4.17. 6-Acetyl-7-methyl-2-(methylsulfanyl)pyrido[2,3-d]py-
rimidine-4(3H)-one (13)
To a stirred solution of aldehyde 1 (500 mg, 2.24 mmol) in
3.5 mL of DMF was added enamine 12 (250 mg, 2.52 mmol)