M. A. Ebraheem et al. / Tetrahedron Letters 51 (2010) 3486–3492
3491
yield (1.2 g, 80%); IR (neat) (
m
max, cmÀ1); 3635, 2928, 1733, 1530,
mp 118–120 °C, IR (KBr) (
m
max, cmÀ1); 3664, 3156, 2995, 2941,
1461; 1H NMR (400 MHz DMSO-d6): d 1.28 (3H, t, –CH3), 2.47
(3H, s, –CH3), 2.49 (3H, s, –SCH3), 3.34 (2H, s, –CH2–), 4.25 (2H,
q, –OCH2CH3); 13C NMR (100 MHz DMSO-d6): d 13.74, 17.89,
33.00, 60.93, 104.18, 126.16, 140.18, 143.53, 158.38, 163.06,
169.90; Anal. Calcd for C11H16N4O4S (302.31): C, 43.99; H, 5.37;
N, 18.65. Found: C, 43.91; H, 5.41; N, 18.57.
1590, 1486; 1H NMR (400 MHz DMSO-d6): d 2.09 (3H, s, –CH3),
2.39 (3H, s, –CH3), 2.50 (3H, s, –SCH3), 6.18 (1H, s, –SH). 13C NMR
(100 MHz DMSO-d6):
d 13.09, 17.05, 31.76, 111.03, 164.03
167.55, 181.40, 197.11; Anal. Calcd for C8H10N2OS2 (214.31): C,
44.84; H, 4.70; N, 13.07. Found: C, 44.75; H, 4.73; N, 12.93.
Ethyl 2-hydroxy-4-methyl-6-(methylthio)pyrimidin-5-carbox-
ylate (4d) obtained as white crystalline solid from (2b) (1.2 g,
5 mmol) and urea (0.30 g, 5 mmol) with yield (0.82 g, 72%), mp
Ethyl 3-ethoxy -5-(methylthio)-1H-pyrazole-4-carboxylate (3d)
obtained as crystalline white solid from (2c) (1.32 g, 5 mmol) and
hydrazine hydrate (0.24 g, 5 mmol) with yield (0.98 g, 86%), mp
48–50 °C; IR (KBr) (m
max, cmÀ1); 3448, 3337, 2985, 2925, 1676,
125–128 °C; IR (KBr) (
m
max, cmÀ1); 3212, 2930, 1665, 1575, 1481;
1533, 1426. 1H NMR (400 MHz DMSO-d6): d 1.27 (3H, t, –CH3),
2.18 (3H, s, –CH3), 2.49 (3H, s, –SCH3), 4.30 (2H, q, –OCH2–), 6.16
(1H, s, –OH); 13C NMR (100 MHz DMSO-d6): d 13.95, 14.25,
16.29, 58.96, 104.19 150.10, 153.30, 161.35, 164.03; Anal. Calcd
for C9H12N2O3S (228.27): C, 47.35; H, 5.30; N, 12.27. Found: C,
47.32; H, 5.32; N, 12.22.
1H NMR (400 MHz DMSO-d6): d 1.14 (3H, t, –CH3), 1.19 (3H, t, –
CH3), 2.21 (3H, s, –SCH3), 3.99 (2H, q, OCH2), 4.01 (2H, q, OCH2),
7.09 (1H, br, –NH); 13C NMR (100 MHz DMSO-d6): d 11.90, 14.79,
57.26, 89.70, 145.50, 164.30, 166.40; Anal. Calcd for C9H14N2O3S
(230.28): C, 46.94; H, 6.13; N, 12.16. Found: C, 46.86; H, 6.19; N,
12.13.
Ethyl 2-mercapto-4-methyl-6-(methylthio) pyrimidin-5-car-
boxylate (4e) obtained as yellow crystalline solid from (2b)
(1.2 g, 5 mmol) and thiourea (0.38 g, 5 mmol) with yield (0.91 g,
4. Synthesis of 1-(4-ethoxy-6-methylpyrimidin-5-yl)ethanone
(4a)
71%), mp 146–148 °C; IR (KBr) (m
max, cmÀ1); 3145, 2974, 1725,
1563, 1443. 1H NMR (400 MHz DMSO-d6): d 1.23 (3H, t, –CH3)
2.05 (3H, s, –CH3), 2.49 (3H, s, –SCH3), 4.21 (2H, q, –OCH2–), 4.26
(2H, q, –OCH2–), 12.26 (1H, br, –SH), 13.28 (1H, br, –NH). 13C
NMR (100 MHz DMSO-d6): d 13.88, 15.91, 18.00, 61.09, 104.04,
110.18 148.04, 158.19, 163.17, 163.70, 173.66, 175.83, 181.69;
Anal. Calcd for C9H12N2O2S2 (244.03): C, 44.24; H, 4.93; N, 11.47.
Found: C, 43.11; H, 4.49; N, 11.36.
a,a-Dioxoketene dithioacetal (2a) (1.02 g, 5 mmol) was added
to a stirred solution of sodium ethoxide (0.01 mol, prepared
in situ from 0.23 g of sodium metal and 5 ml ethanol) in ethanol
(20 ml) at room temperature. After 15 min, Urea (0.30 g, 5 mmol)
was added at the same temperature and the reaction mixture
was refluxed for 3 h. After the reaction, the solvent was evaporated
under reduced pressure and diluted with water (20 ml). It was then
extracted into dichloromethane (2 Â 20 ml) and dried over anhy-
drous Na2SO4. Evaporation of the solvent under reduced pressure
yielded the crude product and later it was purified by column chro-
matography over silica gel using dichloromethane/petroleum ether
(3:1) as eluent.
Ethyl 4-ethoxy-2-hydroxy-6-(methylthio) pyrimidin-5-carbox-
ylate (4f) obtained as red oil from (2c) (1.32 g, 5 mmol) and urea
(0.30 g, 5 mmol) with yield (1.1 g, 85%); IR (neat), (m
max, cmÀ1);
3645, 2983, 1736, 1531, 1445. 1H NMR (400 MHz DMSO-d6): d
1.23 (3H, t, –CH3), 2.45 (2H, s, –SCH3), 4.23 (2H, q, –OCH2), 5.45
(1H, s, –OH), 5.71 (1H, br, –NH), 5.82 (1H, br, –NH). 13C NMR
(100 MHz DMSO-d6): d 13.94, 14.94, 16.67, 61.62, 148.04, 153.26,
158.19, 163.98, 166.42; Anal. Calcd for C10H14N2O4S (258.29): C,
46.50; H, 5.46; N, 10.85. Found: C, 46.44; H, 5.51; N, 10.79.
1-(4-Ethoxy-6-methylpyrimidin-5-yl)ethanone (4a) obtained
as white crystalline solid with yield (0.75 g, 76%), mp 57–60 °C,
IR (KBr) (m
max, cmÀ1): 3284, 3140, 2989, 1623, 1468; 1H NMR
(400 MHz DMSO-d6): d 1.20 (3H, t, –CH3), 2.43 (3H, s, –CH3), 2.49
(3H, s, –CH3), 4.07 (2H, q, –OCH2), 5.57 (1H, s, –OH); 13C NMR
(100 MHz DMSO-d6): d 11.25, 14.19, 30.58, 50.19, 107.24, 145.27,
149.66, 162.93, 206.33; Anal. Calcd for C9H12N2O3 (196.08): C,
55.09; H, 6.16; N, 14.28. Found: C, 55.12; H, 6.14; N, 14.24.
6. General procedure for the synthesis of substituted 2,3,4-
substituted quinolines (5a–c)
Typical procedure for the synthesis of 1-(4-hydroxy-2-(methyl-
thio) quinolin-3-yl)ethanone (5a): To the solution of a,a-dioxoke-
5. General procedure for the synthesis of polysubstituted
(2,4,5,6-pyrimidines) (4b)
tene dithioacetal (2b) (2.34 g, 10 mmol) in ethanol (30 ml), aniline
(0.9 ml 10 mmol) was added. The reaction mixture was refluxed
for 3 h until all starting materials had disappeared as indicated
by TLC. After the reaction, the solvent was removed under pressure
and then water (20 ml) was added. The mixture was then extracted
with chloroform (2 Â 20 ml) followed by washing with water. The
organic layer was dried over anhydrous Na2SO4; solvent was evap-
orated and the product was obtained (5a) as white crystalline solid
with yield (0.92 g, 79%), mp 218–225 °C (sublimate) (from etha-
A
typical procedure for the synthesis of 1-(2-hydroxy-4-
methyl-6-(methylthio)pyrimidin-5-yl)ethanone (4b): To the solu-
tion of -dioxoketene dithioacetal (2a) (1.02 g, 5 mmol) in etha-
a,a
nol (20 ml), urea (0.30 g, 5 mmol) was added. The reaction mixture
was refluxed for 3 h until all starting materials had disappeared as
indicated by TLC. After the reaction, the solvent was removed un-
der pressure and the resultant pasty mass was extracted into
dichloromethane (2 Â 20 ml) followed by washing with water.
The organic layer was dried over anhydrous Na2SO4; solvent was
evaporated and the product (4b) was obtained as white crystalline
nol), IR (KBr) (m
max, cmÀ1); 3321, 3040, 1613, 1446; 1H NMR
(400 MHz DMSO-d6): d 2.48 (3H, s, –CH3), 2.49 (3H, s, –SCH3),
6.97 (1H, t, ArH), 7.28 (1H, t, ArH), 7.44 (1H, d, ArH), 8.61 (1H, s,
–OH). 13C NMR (100 MHz DMSO-d6): d 17.07, 29.00, 109.70,
112.01, 118.13, 121.75, 128.72, 139.64, 145.20, 152,47; Anal. Calcd
for C12H11NO2S (233.05): C, 61.78; H, 4.75; N, 6.00. Found: C,
61.69; H, 4.70; N, 6.09.
1-(6-Chloro-4-hydroxy-2-(methylthio) quinolin-3-yl)ethanone
(5b) obtained as yellow crystalline solid from (2b) (2.34 g,
10 mmol) and 4-chloroaniline (1.3 g, 10 mmol) with yield (0.89 g,
solid with yield (0.70 g, 70%), mp 52–55 °C, IR (KBr) (m
max, cmÀ1);
3262, 2991, 1644, 1525. 1H NMR (400 MHz DMSO-d6): d 2.08
(3H, s, –CH3), 2.38 (3H, s, –CH3), 2.49 (3H, s, –SCH3), 6.17 (1H, s,
–OH); 13C NMR (100 MHz DMSO-d6):
d 13.95, 16.47, 30.05,
113.26, 156.30 161.39, 191.74; Anal. Calcd for C8H18N2O2S
(198.05): C, 48.47; H, 5.08; N, 14.13. Found: C, 48.38; H, 5.12; N,
14.10.
1-(2-Mercapto-4-methyl-6-(methylthio)pyrimidin-5-yl)etha-
none (4c) obtained as white crystalline solid from (2b) (1.2 g,
5 mmol) and thiourea (0.38 g, 5 mmol) with yield (0.66 g, 66%),
66%), mp >120 °C (decomposed), (from ethanol), IR (KBr) (mmax
,
cmÀ1); 3134, 3051, 2999, 1636, 1489; 1H NMR (400 MHz DMSO-
d6): d 2.57 (3H, s, –COCH3), 2.73 (3H, s, –SCH3), 7.30 (2H, m,
ArH), 8.09 (1H, d, ArH), 10.58 (1H, br, –OH), 12.97 (1H, br, –NH).