Jul-Aug 2003
Synthesis and Biological Properties of 4-Substituted Quinolin-2(1H)-one Analogues
621
2H, J=7.1 Hz), 2.42 (s, 3H), 1.30 (t, 3H, J=7.1 Hz); 13C nmr
(dimethyl sulfoxide-d6): d 168.0, 164.9, 152.5, 149.1, 147.4, 143.7,
135.2, 119.9, 110.9, 102.4, 59.0, 13.7, 12.2; ms (m/e): 283 (M+),
hrms calcd. for C13H11F2NO4: 284.0707 (M+ + 1), found 284.0727.
(dd, 1H, J=8.7 Hz, J=7.9 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.16 (q,
2H, J=7.1 Hz), 1.26 (t, 3H, J=7.1 Hz), 1.18 (t, 3H, J=7.1 Hz); 13
nmr (deuteriochloroform): d 169.4, 169.0, 166.2, 158.1, 152.9,
148.2, 120.3, 118.6, 113.8, 95.7, 62.0, 61.9, 14.0, 13.9; ms
(FAB+): 346 (M++1), 274, 186 (base peak), 154, 137; hrms calcd.
for C14H13F2NO7: 346.0738 (M++1), found 346.0734.
C
Ethyl 3,4-Difluoro-2-nitrobenzoylacetate (5a).
A solution of diethyl 4,5-difluoro-2-nitrobenzoylmalonate (2c,
7.0 g, 20.3 mmol) and p-toluenesulfonic acid (0.2 g) in 80 ml of
water was refluxed for 12 h. The reaction mixture was cooled to
room temperature and extracted with 120 ml of ethyl acetate. The
organic layer was washed with 2% sodium bicarbonate and brine,
dried over anhydrous magnesium sulfate, filtered and concen-
trated to give a yellow oil 5.0 g (91%) of 5a, Rf = 0.35 (50% ethyl
acetate in hexane); ir (nmax, chloroform); 3280-3045, 1738, 1605,
Diethyl 2-(4-Chloro-2-nitrobenzoyl)malonate (2d).
This compound was obtained in 98% yield as a yellow liquid,
Rf = 0.31 (33% ethyl acetate in hexane); ir (nmax, chloroform)
3289, 1730, 1687, 1460, 1080, cm-1; 1H nmr (deuteriochloro-
form, ref [21]): d 14.02 (br s, 1H), 8.45 (d, 1H, J=7.0 Hz), 8.22
(d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=7.0 Hz), 4.21 (q, 2H, J=7.1 Hz),
4.18 (q, 2H, J=7.1 Hz), 1.24 (t, 3H, J=7.1 Hz), 1.18 (t, 3H, J=7.1
Hz); 13C nmr (deuteriochloroform): d 170.5, 168.9, 167.3, 158.2,
149.3, 135.1, 121.4, 118.7, 114.8, 96.7, 62.1, 62.1, 14.0, 13.9.
1
1070 cm-1; H nmr (deuteriochloroform): d 8.07 (dd, 1H, J=6.7
Hz, J=6.7 Hz), 7.45 (dd, 1H, J=7.4 Hz, J=7.4 Hz), 4.18 (q, 2H,
J=7.1 Hz), 3.88 (s, 1H), 2.54 (s, 1H), 1.28 (t, 3H, J=7.1 Hz); 13
C
Ethyl 6,7-Difluoro-4-hydroxyquinolin-2(1H)-one-3-carboxylate
(3a).
nmr (deuteriochloroform): d 182.9, 168.3, 159.4, 158.7, 153.6,
133.3, 117.7, 115.9, 61.5, 44.8, 14.0; ms (FAB+) 274 (M++1, base
peak), 186, 137, 89; hrms calcd. for C11H9F2NO5: 274.0527
(M++1), found 274.0528.
To a solution of keto diester 2c (3.5 g, 10 mmol) in dioxane (45
ml) was added 20% aqueous sodium hydroxide (10 ml) and 10%
palladium-on-charcoal (0.4 g) at room temperature. The mixture
was stirred for 20 min, and then added dropwise to a solution of
sodium borohydride (0.7 g, 18.5 mmol) in water (5 ml). The reac-
tion mixture was stirred at room temperature for 30 min, and fil-
tered through Celite. The filtrate was concentrated to remove
dioxane, and the residue was acidified with 10% hydrochloric
acid to give a pale yellow solid, which was recrystallized from
ethanol to give 1.9 g (72%) of 3a, Rf = 0.26 (15% methanol in
chloroform); mp 280 °C (dec); ir (nmax, potassium bromide):
3270-3030, 1649, 1579, 1188 cm-1; 1H nmr (dimethyl sulfoxide-
d6): d 12.86 (br s, 1H), 8.10 (dd, 1H, J=9.3 Hz, J=9.2 Hz), 7.71
(dd, 1H, J=7.0 Hz, J=6.8 Hz), 4.44 (q, 2H, J=7.1 Hz), 1.40 (t, 3H,
J=7.1 Hz); 13C nmr (dimethyl sulfoxide-d6): d 168.2, 165.7,
162.9, 152.1, 148.6, 143.9, 117.2, 112.9, 109.9, 101.9, 61.9, 14.4;
ms (m/e): 269 (M+), 239 (base peak), 171, 143, 115.
Ethyl 4-Chloro-2-nitrobenzoylacetate (5b).
According to the same procedure, compound 5b was obtained
in 72% yield from 2d, Rf = 0.40 (50% ethyl acetate in hexane); ir
1
(nmax, chloroform) 3258-3022, 1726, 1669, 1242 cm-1; H nmr
(deuteriochloroform, ref [23]): d 8.41 (d, 1H, J=7.9 Hz), 8.08 (d,
1H, J=7.1 Hz), 6.97 (d, 1H, J=7.4 Hz), 4.20 (q, 2H, J=7.1 Hz),
3.68 (s, 1 H), 2.59 (s, 1 H), 1.21 (t, 3H, J=7.1 Hz); 13C nmr (deu-
teriochloroform): d 189.3, 170.8, 150.1, 140.2, 135.6, 129.8,
128.4, 122.9, 60.1, 42.3, 13.7.
6,7-Difluoro-4-hydroxyquinolin-2(1H)-one (6a).
The keto ester 5a (5.5 g, 20.1 mmol) in ethanol (120 ml) was
hydrogenated over 10% palladium-on-charcoal (1.0 g) at 36 psi
for 1 h. The mixture was filtered through Celite and evaporated.
A dark yellow solid was obtained, which was recrystallized from
ethanol to give 3.8 g (96%) of 6a, Rf = 0.35 (20% methanol in
chloroform); mp 310 °C (dec); ir (nmax, potassium bromide);
3200-2230, 1685, 1486, 1173 cm-1; 1H nmr (dimethyl sulfoxide-
d6): d 11.65 (br s, 1H), 11.34 (br s, 1H), 7.69 (dd, 1H, J=8.7 Hz,
Anal. Calcd. for C12H9F2NO4: C, 53.54; H, 3.37; N, 5.20.
found C, 53.36; H, 3.51; N, 5.39.
Ethyl 7-Chloro-4-hydroxyquinolin-2(1H)-one-3-carboxylate
(3b).
According to the same procedure, compound 3b was obtained
in 72% yield from 2d, Rf = 0.33 (20% methanol in chloroform);
mp 287°C (dec); ir (nmax, potassium bromide) 3346, 1725, 1684,
1181, cm-1; 1H nmr (dimethyl sulfoxide-d6, ref [22]): d 13.54 (br
s, 1H), 8.23 (dd, 1H, J=8.4 Hz, J=8.3 Hz), 7.86 (dd, 1H, J=7.6 Hz,
J=6.6 Hz), 7.13 (d, 1H, J=6.9 Hz), 4.31 (q, 2H, J=7.1 Hz), 1.37 (t,
3H, J=7.1 Hz); 13C nmr (dimethyl sulfoxide-d6): d 167.8, 166.5,
163.8, 156.2, 147.5, 143.4, 116.3, 113.9, 111.0, 102.0, 62.0, 14.1;
J=8.7 Hz), 7.21 (dd, 1H, J=7.0 Hz, J=7.0 Hz), 5.76 (s, 1H); 13
C
nmr (dimethyl sulfoxide-d6): d 163.4, 152.8, 149.5, 146.3, 143.1,
136.4, 110.5, 103.3, 98.6; ms (m/e) 197 (M+); hrms: calcd. for
197.0288 (M+), found 197.0291.
Anal. calcd. for C9H5F2NO2: C, 54.83; H, 2.56; N, 7.10. found
C, 54.89; H, 2.51; N, 7.23.
7-Chloro-4-hydroxyquinolin-2(1H)-one (6b).
According to the same procedure, compound 6b was obtained
in 88% yield from 5b, Rf = 0.32 (20% methanol in chloroform);
mp 300 °C (dec), {(ref [24], mp 279 °C (dec)}; ir (nmax, potas-
Ethyl 6,7-Difluoro-1-hydroxy-2-methyl-1,4-dihydro-4-oxo-
quinoline-3-carboxylate (4).
1
sium bromide) 3327, 1694, 1516, 1072 cm-1; H nmr (dimethyl
A solution of the diketo ester 2a (3.2 g, 10.2 mmol) in ethanol (80
ml) was hydrogenated over 10% palladium-on-charcoal (0.6 g)
under atmospheric pressure at room temperature for 3 h. The reac-
tion mixture was filtered through Celite and evaporated to give a
pale yellow solid, which was recrystallized from ethanol to give 2.2
g (78%) of 4, Rf = 0.33 (10% methanol in chloroform); mp 202 °C;
ir (nmax, potassium bromide): 3450, 1717, 1605, 1475, 1110 cm-1;
1H nmr (dimethyl sulfoxide-d6): d 12.33 (br s, 1H), 8.04 (dd, 1H,
J=10.1 Hz, J=8.4 Hz), 7.91 (dd, 1H, J=7.1 Hz, J=6.8 Hz), 4.26 (q,
sulfoxide-d6): d 12.85 (br s, 1H), 11.22 (br s, 1H), 7.69 (d, 1H,
J=8.0 Hz), 7.35 (d, 1H, J=7.2 Hz), 5.83 (s, 1 H); 13C nmr
(dimethyl sulfoxide-d6): d 168.3, 154.2, 151.0, 145.4, 141.3,
135.3, 109.1, 104.9, 99.6.
6,7-Difluoro-3-nitro-4-hydroxyquinolin-2(1H)-one (7a).
A solution of 6a (1.1 g, 5.6 mmol), nitric acid (70%, 12 ml,
8.0 mmol) and glacial acetic acid (8 ml) was heated at 90 °C