64
J.-C. Jung, Y.-J. Jung and O.-S. Park
Vol. 38
mixture was cooled to 5°. The former solution was cannulated
into the latter. The resulting reaction mixture was stirred at room
temperature for 30 minutes and then 20 ml of 10% hydrochloric
acid was added. The mixture was extracted with ether, and the
combined organic extracts were washed with brine, dried and
concentrated at reduced pressure.
Ethyl 4-hydroxyquinolin-2(1H)-3-carboxylate (5a).
To a solution of keto diester 4a (3.1 g, 10.0 mmoles) 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 minutes and then
added dropwise to a solution of sodium borohydride (0.7 g, 18
mmoles) in water (5 ml). The reaction mixture was stirred at
room temperature under hydrogen gas for 30 minutes and filtered
through Celite. The filtrate was concentrated to remove dioxane
and then the residue was acidified with 10% hydrochloric acid to
give a pale yellow solid, which was recrystallized from ethanol to
give 1.6 g (70%) of 5a, mp 300° (dec, ref [19], 304°); ir
Diethyl 2-nitrobenzoylmalonate (4a).
This compound was obtained in 99% yield as a beige liquid
(ref [18]), ir (chloroform); 3428, 2964, 1726, 1702, 1455, 1196
-1 1
cm ; H nmr (deuteriochloroform): δ 14.53 (br s, 1H), 7.82-7.46
(m, 3H), 7.38 (d, 1H, J = 7.06 Hz), 4.18 (q, 2H, J = 7.12 Hz), 4.10
(q, 2H, J = 7.14 Hz), 1.26 (t, 3H, J = 7.12 Hz), 1.11 (t, 3H, J =
-1
1
potassium bromide); 3320-3084, 1711, 1412, 1144 cm ; H nmr
13
7.14 Hz); C nmr (deuteriochloroform): δ 176.1, 169.7, 166.2,
(dimethyl sulfoxide-d ): δ 12.64 (br s, 1H), 8.22-8.01 (m, 3H),
6
152.3, 133.9, 130.6, 126.8, 125.1, 119.2, 97.4, 62.4, 61.8, 14.2,
14.0.
7.95 (d, 1H, J = 6.97 Hz), 4.26 (q, 2H, J = 7.11 Hz), 1.30 (t, 3H,
13
J= 7.11 Hz); C nmr (dimethyl sulfoxide-d ): δ 172.3, 171.4,
6
164.2, 151.1, 129.2, 126.3, 125.7, 120.2, 105.1, 99.0, 59.8, 13.9.
According to the same procedure, ethyl 6,7-difluoro-4-hydroxy-
quinolin-2(1H)-one-3-carboxylate (5b) was prepared. Compound
5b was obtained in 72% yield from 4b, mp 280° (dec); ir (potassium
Diethyl 4,5-difluoro-2-nitrobenzoylmalonate (4b).
This compound was obtained in 95% yield as a yellow liquid,
-1
1
ir (chloroform); 3390, 1703, 1687, 1460, 1080, cm ; H nmr
(deuteriochloroform): δ 13.26 (br s, 1H), 8.11 (dd, 1H, J = 7.09
Hz, J = 6.93 Hz), 7.33 (dd, 1H, J = 8.69 Hz, J = 7.92 Hz), 4.24
(q, 2H, J = 7.13 Hz), 4.16 (q, 2H, J = 7.12 Hz), 1.26 (t, 3H, J =
-1
1
bromide); 3270-3030, 1649, 1579, 1188 cm ; H nmr (dimethyl
sulfoxide-d ): δ 12.86 (br s, 1H), 8.10 (dd, 1H, J = 9.34 Hz, J = 9.17
6
Hz), 7.71 (dd, 1H, J =7.01 Hz, J = 6.79 Hz), 4.44 (q, 2H, J = 7.13
13
7.13 Hz), 1.18 (t, 3H, J = 7.12 Hz); C nmr (deuterio-
13
Hz), 1.40 (t, 3H, J = 7.13 Hz); C nmr (dimethyl sulfoxide-d ): δ
6
chloroform): δ 169.4, 168.9, 166.2, 158.1, 152.9, 148.2, 120.3,
168.2, 165.6 162.8, 152.0, 148.5, 143.9, 117.2, 112.9, 109.8, 101.9,
+
+
118.6, 113.8, 95.7, 62.0, 61.9, 14.0, 13.8; ms (fab ) 346 (M +1),
274, 186 (base peak), 154, 137; hrms: calcd. for 346.0738, found
+
61.8, 14.3; ms (m/e) 269 (M ), 239 (base peak), 171, 143, 115.
Anal. Calcd. for C H N: C, 53.54; H, 3.37; N, 5.20. Found C,
12
9
+
346.0734 (M +1).
55.36; H, 3.51; N, 5.39.
Ethyl 2-nitrobenzoylacetoacetate (4c).
Ethyl 1-hydroxy-2-methyl-4-oxoquinoline-3-carboxylate (6a).
This compound was obtained in 98% yield as a yellow liquid
(ref [18]), ir (chloroform); 3368, 2951, 1726, 1706, 1454, 1088
cm ; H nmr (deuteriochloroform): δ 13.84 (br s, 1H), 7.69-7.40
A solution of the diketo ester 4c (2.8 g, 10.2 mmoles) in 80 ml
of ethanol was hydrogenated over 10% palladium-on-charcoal
(0.5 g) under atmospheric pressure at room temperature for
2 hours. The reaction mixture was filtered through Celite and
evaporated to give a pale yellow solid, which was recrystallized
from ethanol to give 1.9 g (77%) of 6a, mp 198°; ir (potassium
-1 1
(m, 3H), 7.32 (d, 1H, J = 6.98 Hz), 4.22 (q, 2H, J = 7.13 Hz), 2.43
13
(s, 3H), 1.28 (t, 3H, J = 7.13 Hz); C nmr (deuteriochloroform):
δ 192.5, 174.8, 173.2, 150.6, 133.4, 128.9, 126.8, 125.7, 120.1,
100.6, 61.2, 21.4, 14.1.
-1 1
bromide); 3508, 1713, 1588, 1246, 1096 cm ; H nmr (dimethyl
sulfoxide-d ): δ 13.43 (br s, 1H), 12.25 (br s, 1H), 8.29 (d, 1H,
6
Ethyl 4,5-difluoro-2-nitrobenzoylacetoacetate (4d).
J= 7.94 Hz), 7.64-7.40 (m, 3H), 4.23 (q, 2H, J = 7.12 Hz), 2.32
This compound was obtained in 97% yield as a yellow liquid,
ir (chloroform); 3405, 1712, 1639, 1437, 1014 cm ; H nmr
13
(s, 3H), 1.30 (t, 3H, J = 7.12 Hz); C nmr (dimethyl
-1
1
sulfoxide d ): δ 171.2, 166.5, 154.1, 150.8, 135.4, 128.1, 126.4,
6
(dimethyl sulfoxide-d ): δ 13.55 (br s, 1H), 8.47 (dd, 1H, J = 6.99
120.9, 110.3, 101.7, 57.8, 14.1, 12.7.
6
Hz, J = 6.95 Hz), 7.83 (dd, 1H, J = 7.77 Hz, J = 7.75 Hz), 3.90
(q, 2H, J = 7.09 Hz), 2.45 (s, 3H), 0.86 (t, 3H, J = 7.09 Hz);
Ethyl 6,7-difluoro-1-hydroxy-2-methyl-4-oxoquinoline-3-
carboxylate (6b).
13
C
nmr (dimethyl sulfoxide-d ): δ 192.3, 173.6, 165.8, 157.2, 155.0,
6
+
149.8, 119.6, 118.5, 113.4, 100.3, 58.9, 24.2, 13.4; ms (fab ) 316
A solution of the diketo ester 4d (3.2 g, 10.2 mmoles) in 80 ml
of ethanol was hydrogenated over 10% palladium-on-charcoal
(0.6 g) under atmospheric pressure at room temperature for
6 hours. The reaction 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 6b, mp 202°; ir (potassium
+
(M +1, base peak), 270, 186, 137; hrms: calcd. for 316.0633,
+
found 316.0632 (M +1).
Ethyl 2-benzoyl-3-(4,5-difluoro-2-nitrophenyl)-3-oxopro-
panonate (4e).
-1
1
This compound was obtained in 98% yield as a beige liquid, ir
(chloroform); 3378, 1711, 1604, 1541, 1411, 1148 cm ; H nmr
bromide); 3450, 1717, 1605, 1475, 1110 cm ; H nmr (dimethyl
-1
1
sulfoxide-d ): δ 12.33 (br s, 1H), 8.04 (dd, 1H, J = 10.07 Hz, J =
6
(dimethyl sulfoxide-d ): δ 13.60 (br s, 1H), 8.62 (dd, 1H, J = 7.16
Hz, J = 7.13 Hz), 8.15-8.05 (m, 3H), 7.95 (dd, 1H, J = 7.93 Hz,
8.44 Hz), 7.91 (dd, 1H, J = 7.09 Hz, J = 6.77 Hz), 4.26 (q, 2H, J =
7.10 Hz), 2.42 (s, 3H), 1.30 (t, 3H, J = 7.10 Hz); C nmr
6
13
J= 7.92 Hz), 7.67-7.60 (m, 2H), 3.94 (q, 2H, J = 7.15 Hz), 0.89
(dimethyl sulfoxide-d ): δ 168.0, 164.8, 152.5, 149.1, 147.3,
6
13
(t, 3H, J = 7.15 Hz); C nmr (dimethyl sulfoxide-d ): δ 193.6,
143.6, 135.2, 119.8, 110.9, 102.3, 58.9, 13.6, 12.1; ms (m/e) 283
6
+
+
173.1, 170.7, 158.0, 152.5, 150.2, 136.4, 133.8, 133.3, 129.8,
(M ), hrms: calcd. for 283.0707, found 283.0727 (M ).
+
129.1, 127.6, 120.2, 118.7, 112.9, 95.8, 60.0, 13.9; ms (fab ) 378
According to the same procedure, ethyl 6,7-difluoro-1-
hydroxy-2-phenyl-4-oxoquinoline-3-carboxylate (6c) was
prepared. Compound 6c was obtained in 71% yield from 4e, mp
+
(M +1, base peak), 332, 274, 193, 105, 77; hrms: calcd. for
+
378.0789, found 378.0789 (M +1).