SAR of Tetrahydroquinoline-2,3,4-trione 3-Oximes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3253
The solution was evaporated to give a solid which was treated
with 100 mL of water. The mixture was filtered, washed with
water (3 × 15 mL), 10% NaHCO3 (15 mL), and water (3 × 15
mL), and dried in vacuo to give 3.5 g (94%) of methyl 2-amino-
4-chlorobenzoate as a white solid: mp 66-68 °C; 1H NMR
(CDCl3) 3.86 (s, 1H), 5.56 (bs, 2H), 6.56 (d, J ) 8.7, 1H), 6.67
(s, 1H), 7.76 (d, J ) 8.4, 1H).
11.52 (s, 0.5H), 14.97 (s, 0.5H), 15.64 (s, 0.5H); 1H NMR
(DMSO-d6 + D2O) 7.12 (m, 1H), 7.64-7.78 (m, 2H); HRMS
calcd for C9H535ClN2O3 223.9985, found 223.9991. Anal.
(C9H5ClN2O3‚0.2H2O) C, H; N: calcd, 12.30; found, 11.86.
5-Ch lor o-1,2,3,4-tetr a h yd r oqu in olin e-2,3,4-tr ion e 3-ox-
1
im e (11d ): mp 220-222 °C dec; H NMR (DMSO-d6) 7.04-
7.18 (m, 2H), 7.49 (m, 1H), 11.20 (s, 0.5H), 11.43 (s, 0.5 H);
HRMS calcd for C9H535ClN2O3 223.9985, found 223.9984.
Anal. (C9H5ClN2O3) C, H, N.
A solution of 2.095 g (11.3 mmol) of methyl 2-amino-4-
chlorobenzoate and acetic anhydride (12.5 mL) in dry dioxane
(20 mL) was heated (50 °C) under nitrogen for 3 h. Water (5
mL) was then added, and the solution was evaporated to leave
a white solid which was collected by filtration and dried to
give 1.976 g (77%) of methyl 2-acetamido-4-chlorobenzoate: mp
8-Ch lor o-1,2,3,4-tetr a h yd r oqu in olin e-2,3,4-tr ion e 3-ox-
im e (11e): mp 180-182 °C; 1H NMR (DMSO-d6) 7.11 (m, 1H),
7.72 (m, 2H), 10.31 (s, 0.5H), 10.51 (s, 0.5H); HRMS calcd for
C9H535ClN2O3 223.9985, found 223.9986. Anal. (C9H5ClN2-
O3‚0.1H2O) C, H, N.
5,7-Dim e t h yl-1,2,3,4-t e t r a h yd r oq u in olin e -2,3,4-t r i-
on e 3-oxim e (11j): mp 228-230 °C; 1H NMR (DMSO-d6) 2.27
(s, 1.4H), 2.28 (s, 1.6H), 2.54 (s, 1.4H), 2.57 (s, 1.6H), 6.75-
6.82 (m, 2H), 11.07 (s, 0.54H), 11.37 (s, 0.46H); HRMS calcd
1
121-123 °C; H NMR (CDCl3) 2.24 (s, 3H), 3.93 (s, 3H), 7.03
(dd, J ) 8.7, 1.8, 1H), 7.94 (d, J ) 8.7, 1H), 8.81 (d, J ) 1.8,
1H), 11.10 (s, 1H).
A solution of 113.8 mg (0.5 mmol) of methyl 2-acetamido-
4-chlorobenzoate in dry THF (2 mL) was added dropwise into
a solution of potassium bis(trimethylsilyl)amide in toluene (3
mL, 1.5 mmol) at -78 °C under nitrogen. The reaction
mixture was then allowed to warm to room temperature and
stirred at room temperature for 12 h. The mixture was poured
into ice/water (5 mL). The aqueous layer was washed with
ethyl acetate (5 mL) and acidified (pH ) 2) to give a white
solid which was collected by filtration and dried in vacuo,
giving 80 mg (82%) of 10b: mp 278-280 °C dec (lit.30 mp 279
for C11H10N2O3 218.0690, found 218.0682. Anal. (C11H10
-
N2O3‚0.4H2O) C, H, N.
7-Ch lor o-6,8-diflu or o-1,2,3,4-tetr ah ydr oqu in olin e-2,3,4-
1
tr ion e 3-oxim e (11k ): mp 240 °C dec; H NMR (DMSO-d6)
7.68 (m, 1H), 11.34 (bm, 0.6H), 11.50 (bm, 0.4H); HRMS calcd
for C9H335ClF2N2O3 259.9797, found 259.9785. Anal. (C9H3-
ClF2N2O3) C, H; N: calcd, 10.75; found, 10.20.
5,6,7,8-Tet r a flu or o-1,2,3,4-t et r a h yd r oq u in olin e-2,3,4-
tr ion e 3-oxim e (11l): mp 220-221 °C dec; 1H NMR (DMSO-
d6) 11.48 (s, 0.7H), 11.54 (m, 0.3H); HRMS calcd for C9H2F4N2O3
261.9999, found 261.9981. Anal. (C9H2F4N2O3) C, H, N.
5,6-Dich lor o-1,2,3,4-t et r a h yd r oq u in olin e-2,3,4-t r ion e
3-Oxim e (11f) a n d 6,7-Dich lor o-1,2,3,4-tetr a h yd r oqu in o-
lin e-2,3,4-tr ion e 3-Oxim e (11h ). A mixture of 113 mg (0.491
mmol) of 10f,h and 120 mg (1.73 mmol) of NaNO2 in 3 mL of
0.2 N NaOH was stirred for 30 min. To the resulting solution
was added dropwise 1 mL of 2 N H2SO4. The resulting red
mixture was stirred overnight, filtered and washed with water,
and dried to leave 111 mg of a yellow solid. 1H NMR showed
11f:11h ) 1:1. The solid was boiled with 15 mL of 95% ethanol
and 2 mL of acetone, and the mixture was filtered. The solid
in the filter was dried to leave 20 mg (15.7%) of 11h as a yellow
solid: mp > 250 °C; 1H NMR (CDCl3 + DMSO-d6) 6.99 (s,
0.4H), 7.01 (s, 0.6H), 7.66 (s, 0.4H), 7.73 (s, 0.6H), 11.10 (s,
0.4H), 11.55 (s, 0.6H); HRMS calcd for C9H435Cl2N2O3 257.9595,
found 257.9611. Anal. (C9H4Cl2N2O3) H; C: calcd, 41.73;
found, 42.46. N: calcd, 10.81; found, 10.21.
1
°C); H NMR (DMSO-d6) 5.69 (s, 1H), 7.11 (dd, J ) 8.6, 1.8,
1H), 7.24 (d, J ) 1.8, 1H), 7.71 (d, J ) 8.6, 1H), 11.25 (s, 1H),
11.46 (s, 1H); HRMS calcd for C9H635ClNO2 195.0084, found
195.0079.
Compounds 10c-e were similarly prepared from the cor-
responding chloro-substituted 2-aminobenzoic acids.
6-Ch lor o-2,4-qu in olin ed iol (10c): mp 342-344 °C dec
(lit.28 mp > 360 °C); 1H NMR (DMSO-d6) 5.72 (s, 1H), 7.22 (d,
J ) 8.7, 1H), 7.48 (dd, J ) 8.7, 2.4, 1H), 7.68 (d, J ) 2.4, 1H),
11.30 (s, 1H), 11.50 (s, 1H); HRMS calcd for C9H635ClNO2
195.0084, found 195.0088.
5-Ch lor o-2,4-qu in olin ed iol (10d ): mp 346-348 °C dec;
1H NMR (DMSO-d6) 5.74 (s, 1H), 7.11 (d, J ) 7.5, 1H), 7.18
(d, J ) 8.4, 1H), 7.34 (dd, J ) 8.4, 7.5, 1H), 11.34 (s, 1H), 11.37
(s, 1H); HRMS calcd for C9H635ClNO2 195.0084, found 195.0088.
8-Ch lor o-2,4-qu in olin ed iol (10e): mp 280-282 °C dec
1
(lit.28 mp 305 °C); H NMR (DMSO-d6) 5.76 (s, 1H), 7.10 (dd,
J ) 8.1, 7.2, 1H), 7.61 (d, J ) 7.2, 1H), 7.76 (d, J ) 8.1, 1H),
10.36 (s, 1H), 11.60 (s, 1H); HRMS calcd for C9H635ClNO2
195.0084, found 195.0083.
A solid precipitate was observed in the filtrate after it was
cooled to room temperature. The precipitate was collected by
filtration, washed with a minimum amount of ethanol, and
dried to leave 37 mg of a yellow solid which was a mixture of
11f,h as determined by 1H NMR. A second crop of precipitate
was observed in the filtrate. The precipitate was filtered and
dried to leave 40 mg (31%) of 11f as a yellow-orange solid:
5,7-Dich lor o-1,2,3,4-t et r a h yd r oq u in olin e-2,3,4-t r ion e
3-Oxim e (11g). To a mixture of 147 mg (0.616 mmol) of 5,7-
dichloro-2,4-quinolinediol (10g) and 126 mg (1.82 mmol) of
sodium nitrite in 3 mL of 0.2 N NaOH in an ice bath was added
dropwise 2 mL of aqueous 2 N H2SO4. The mixture was stirred
in the ice bath for 4 h after addition of H2SO4, filtered, and
dried to leave an orange solid. The solid was crystallized by
boiling with 10 mL of ethanol (95%). The solution was cooled
to room temperature, filtered, and dried to leave 132 mg (83%)
of 11g as a yellow solid: mp 244-245 °C dec; 1H NMR (CDCl3
+ DMSO-d6) 7.01 (d, J ) 1.8, 0.44H), 7.08 (m, 1.54H), 11.57
(bs, 0.45H), 11.82 (s, 0.55H); HRMS calcd for C9H435Cl2N2O3
257.9595, found 257.9598. Anal. (C9H4Cl2N2O3) C, H; N:
calcd, 10.81; found, 10.36.
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mp 218-219 °C; H NMR (DMSO-d6) 7.10 (d, J ) 8.6, 0.5H),
7.12 (d, J ) 8.8, 0.5H), 7.79 (d, J ) 8.8, 0.5H), 7.83 (d, J ) 8.8,
0.5H), 11.29 (s, 0.5H), 11.47 (s, 0.5H). Anal. (C9H4Cl2N2-
O3‚0.6H2O) C, H, N.
5,6,7-Tr ich lor o-1,2,3,4-t et r a h yd r oq u in olin e-2,3,4-t r i-
on e 3-Oxim e (11i). To a solution of 228 mg (0.86 mmol) of
10i in t-BuOH (15 mL) were added t-BuOK (488 mg, 4.35
mmol) and isoamyl nitrite (0.585 mL, 4.35 mmol). The
resulting mixture was stirred for 12 h at room temperature
under N2, and then cooled water (10 mL) was added slowly
with stirring. To the resulting deep yellow solution was added
0.5 N HCl to adjust the pH to 2. The precipitate was filtered,
washed with H2O (6 × 10 mL), and dried at 40 °C under 0.1
mmHg for 10 h to give 220 mg (87%) of 11i as a yellow
Compounds 11a -e,j-l were similarly prepared from the
corresponding 2,4-quinolinediols 10.
1,2,3,4-Tetr a h yd r oqu in olin e-2,3,4-tr ion e 3-oxim e (11a ):
mp 206 °C dec (lit.21 mp 208 °C dec); 1H NMR (CDCl3 + DMSO-
d6) 6.65-6.78 (m, 2H), 7.15 (m, 1H), 7.56 (d, J ) 8.1, 0.3H),
7.61 (d, J ) 8.1, 0.7H), 10.89 (s, 0.3H), 11.35 (s, 0.7H); HRMS
calcd for C9H6N2O3 190.0375, found 190.0400. Anal. (C9H6N2-
O3) C, H, N.
7-Ch lor o-1,2,3,4-tetr a h yd r oqu in olin e-2,3,4-tr ion e 3-ox-
im e (11b): mp 230-232 °C dec; 1H NMR (DMSO-d6) 7.10 (m,
2H), 7.81 (m, 1H), 11.18 (s, 0.5H), 11.40 (s, 0.5H); HRMS calcd
for C9H535ClN2O3 223.9985, found 223.9993. Anal. (C9H5-
ClN2O3‚0.45H2O) C, H, N.
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powder: mp 270 °C dec; H NMR (DMSO-d6) 7.31 (s, 1H),
11.34 (s, 0.5H), 11.43 (s, 0.5H); HRMS calcd for C9H335Cl3N2O3
291.9210, found 291.9213. Anal. (C9H3Cl3N2O3) C, H, N.
5,7-Dim et h yl-1,4-d ih yd r oq u in oxa lin e-2,3-d ion e (12j).
A solution of 1.66 g (10 mmol) of 4,6-dimethyl-2-nitroaniline
in 35 mL of ethanol with 200 mg of 10% Pd/C was hydroge-
nated at 25 psi for 2 h. The catalyst was removed by filtration,
and evaporation of the solvent gave 1.30 g (96%) of the
diamine. A solution of 424 mg (3.12 mmol) of the diamine and
432 mg (3.43 mmol) of oxalic acid dihydrate in 20 mL of 4 N
6-Ch lor o-1,2,3,4-tetr a h yd r oqu in olin e-2,3,4-tr ion e 3-ox-
im e (11c): mp 245-247 °C dec (lit.31 mp 163 °C); 1H NMR
(DMSO-d6) 7.15 (m, 1H), 7.68-7.81 (m, 2H), 11.22 (s, 0.5H),