July 2001
827
1234. FAB-MS m/z: 276 (MϩH)ϩ. Rf: 0.21 (hexane/AcOEtϭ1/1). Anal.
Calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26. Found: C, 60.93; H,
6.14; N, 15.15.
67.65; H, 6.23; N, 7.96.
6-Methoxy-7-nitro-3,4-dihydroquinolin-2(1H)-one (17) To a stirred
solution of 16 (1.0 g, 5.64 mmol) in TFA (20 ml), NaNO2 (0.389 g,
5.64 mmol) was added portionwise at 0 °C, and the stirring was continued
for 0.5 h at room temperature. The reaction mixture was poured into ice
water. The precipitate was collected by filtration, washed with Et2O and
dried in vacuo over P2O5 to give 17 (1.11 g, 88%) as a light yellow solid. Re-
crystallization was achieved from Et2O–AcOEt–MeOH. mp 238—241 °C.
1H-NMR (DMSO-d6) d: 2.44—2.51 (m, 2H), 2.94—3.01 (m, 2H), 3.88 (s,
3H), 7.28 (s, 1H), 7.38 (s, 1H), 10.17 (s, 1H). IR (KBr) cmϪ1: 1676, 1522,
1346, 1263. FAB-MS m/z: 223 (MϩH)ϩ. Rf: 0.46 (CH2Cl2/MeOHϭ10/1).
Anal. Calcd for C10H10N2O4: C, 54.05; H, 4.54; N, 12.61. Found: C, 53.84;
H, 4.54; N, 12.50.
6-Hydroxy-7-nitro-3,4-dihydroquinolin-2(1H)-one (18) To a solution
of 17 (1.1 g, 4.95 mmol) in 1,2-dichloroethane (20 ml), Aluminum chloride
(AlCl3) (0.79 g, 5.92 mmol) was added portionwise, and the mixture was re-
fluxed for 0.5 h. To this mixture, additional AlCl3 (0.79 g, 5.92 mmol) was
added portionwise. After further stirring for 1 h at the same temperature, the
reaction mixture was evaporated in vacuo. The concentrate was quenched by
adding H2O. The precipitate was collected by filtration, washed with Et2O
and dried in vacuo over P2O5 to give 18 (1.0 g, 97%) as a yellow solid. Re-
crystallization was achieved from CH2Cl2–Et2O–MeOH. mp 235—238 °C.
1H-NMR (DMSO-d6) d: 2.40—2.48 (m, 2H), 2.88—2.95 (m, 2H), 6.99 (s,
1H), 7.41 (s, 1H), 10.15 (s, 1H), 10.55 (s, 1H). IR (KBr) cmϪ1: 1668, 1537,
1387, 1257. FAB-MS m/z: 209 (MϩH)ϩ. Rf: 0.25 (CH2Cl2/MeOHϭ50/1).
Anal. Calcd for C9H8N2O4: C, 51.93; H, 3.87; N, 13.46. Found: C, 51.71; H,
3.92; N, 13.23.
7-Nitro-6-(4-oxopiperidino)-3,4-dihydroquinolin-2(1H)-one
(22c)
The title compound was obtained as an orange solid (4%), starting from 4-
piperidone monohydrate hydrochloride and following the method as de-
scribed for 22a. Recrystallization was achieved from hexane–AcOEt. mp
251—252 °C. 1H-NMR (CDCl3) d: 2.61—2.69 (m, 6H ), 2.98—3.07 (m,
2H), 3.30—3.37 (m, 4H), 7.06 (s, 1H), 7.31 (s, 1H), 8.66 (br, 1H). IR (KBr)
cmϪ1: 1718, 1684, 1533, 1377, 1334, 1281. FAB-MS m/z: 290 (MϩH)ϩ. Rf:
0.31 (AcOEt). Anal. Calcd for C14H15N3O4: C, 58.13; H, 5.23; N, 14.53.
Found: C, 57.97; H, 5.26; N, 14.29.
6-(4-Formylpiperidino)-7-nitro-3,4-dihydroquinolin-2(1H)-one (22d)
The title compound was obtained as an orange solid (4%), starting from 26
and following the method as described for 23. Recrystallization was
achieved from hexane–AcOEt. mp 211—212 °C. 1H-NMR (CDCl3) d:
1.83—1.95 (m, 2H), 1.98—2.07 (m, 2H), 2.36—2.46 (m, 1H), 2.63—2.69
(m, 2H), 2.83—2.92 (m, 2H), 2.96—3.03 (m, 2H), 3.17—3.22 (m, 2H), 7.00
(s, 1H), 7.27 (s, 1H), 8.24 (br, 1H), 9.71 (s, 1H). IR (KBr) cmϪ1: 1720,
1664, 1522, 1377, 1323, 1288. FAB-MS m/z: 304 (MϩH)ϩ. Rf: 0.38
(AcOEt). Anal. Calcd for C15H17N3O4·0.3H2O: C, 58.36; H, 5.75; N, 13.61.
Found: C, 58.49; H, 5.62; N, 13.31.
6-(4-Acetylpiperidino)-7-nitro-3,4-dihydroquinolin-2(1H)-one (22e)
The title compound was obtained as an orange solid (12%), starting from 29
and following the method as described for 23. Recrystallization was
achieved from hexane–AcOEt. mp 182—183 °C. 1H-NMR (CDCl3) d:
1.80—1.90 (m, 2H), 1.93—2.00 (m, 2H), 2.20 (s, 3H), 2.40—2.48 (m, 1H),
2.62—2.69 (m, 2H), 2.79—2.88 (m, 2H), 2.96—3.03 (m, 2H), 3.22—3.28
(m, 2H), 6.99 (s, 1H), 7.25 (s, 1H), 7.64 (br, 1H). IR (KBr) cmϪ1: 1701,
1676, 1508, 1381, 1317, 1273. FAB-MS m/z: 318 (MϩH)ϩ. Rf: 0.33
(AcOEt). Anal. Calcd for C16H19N3O4·0.3H2O: C, 59.54; H, 6.12; N, 13.02.
Found: C, 59.66; H, 5.82; N, 13.17.
7-Nitro-6-trifluoromethanesulfonyloxy-3,4-dihydroquinolin-2(1H)-
one (19) To a solution of 18 (0.40 g, 1.92 mmol) in DMF (4 ml), Et3N
(0.29 ml, 2.09 mmol) was added at 0 °C. After the mixture was stirred at
0 °C for 5 min, CF3SO2Cl (0.22 ml, 2.09 mmol) was added, and stirring was
continued for 18 h at room temperature. The reaction mixture was parti-
tioned between AcOEt and saturated aqueous NH4Cl. The organic layer was
washed with brine, dried and evaporated. Silica gel column chromatography
(hexane/AcOEtϭ2/1) of the concentrate gave 19 (0.52 g, 79%) as a colorless
powder. Recrystallization was achieved from hexane–AcOEt. mp 187—
6-(4-Ethoxycarbonylpiperidino)-7-nitro-3,4-dihydroquinolin-2(1H)-
one (20f) The title compound was obtained as orange plates (46%), start-
ing from ethyl isonipecotate and following the method as described for 22a.
1
Recrystallization was achieved from hexane–AcOEt. mp 173—175 °C. H-
1
188 °C. H-NMR (DMSO-d6) d: 2.51—2.58 (m, 2H), 3.04—3.11 (m, 2H),
NMR (CDCl3) d: 1.28 (t, Jϭ7.1 Hz, 3H), 1.87—2.06 (m, 4H), 2.38—2.48
(m, 1H), 2.61—2.69 (m, 2H), 2.78—2.87 (m, 2H), 2.96—3.03 (m, 2H),
3.17—3.25 (m, 2H), 4.17 (q, Jϭ7.1 Hz, 2H), 6.99 (s, 1H), 7.25 (s, 1H), 7.78
(br, 1H). IR (KBr) cmϪ1: 1736, 1678, 1516, 1375, 1323, 1282. FAB-MS m/z:
348 (MϩH)ϩ. Rf: 0.47 (AcOEt). Anal. Calcd for C17H21N3O5: C, 58.78; H,
6.09; N, 12.10. Found: C, 58.76; H, 6.06; N, 12.09.
7.67 (s, 1H), 7.71 (s, 1H), 10.60 (s, 1H). IR (KBr) cmϪ1: 1685, 1535, 1423,
1346, 1207. FAB-MS m/z: 341 (MϩH)ϩ. Rf: 0.18 (hexane/AcOEtϭ3/1).
Anal. Calcd for C10H7F3N2O6S: C, 35.30; H, 2.07; N, 8.23. Found: C, 35.25;
H, 2.14; N, 8.29.
7-Nitro-6-thiomorpholino-3,4-dihydroquinolin-2(1H)-one (22a)
A
solution of 19 (357 mg, 1.05 mmol) and thiomorpholine (0.53 ml, 5.25
mmol) in CH3CN (10 ml) was stirred at 80 °C for 4 h. The reaction mixture
was concentrated in vacuo. Preparative TLC (silica gel, hexane/AcOEtϭ2/1)
of the residue gave 22a (156 mg, 51%) as an orange solid. Recrystallization
6-(4-Cyanopiperidino)-7-nitro-3,4-dihydroquinolin-2(1H)-one (22g)
The title compound was obtained as orange plates (20%), starting from 28
and following the method as described for 23. Recrystallization was
achieved from hexane–AcOEt. mp 241—242 °C. 1H-NMR (CDCl3) d:
1.97—2.13 (m, 4H), 2.63—2.70 (m, 2H), 2.83—2.91 (m, 1H), 2.96—3.05
(m, 4H), 3.13—3.22 (m, 2H), 7.05 (s, 1H), 7.28 (s, 1H), 8.38 (s, 1H). IR
(KBr) cmϪ1: 2237, 1678, 1522, 1373, 1336, 1282. FAB-MS m/z: 301
(MϩH)ϩ. Rf: 0.18 (hexane/AcOEtϭ1/2). Anal. Calcd for C15H16N4O3·
0.3H2O: C, 58.93; H, 5.47; N, 18.33. Found: C, 59.23; H, 5.31; N, 18.04.
1-tert-Butoxycarbonyl-4-(hydroxymethyl)piperidine (25) To a stirred
solution of 4-(hydroxymethyl)piperidine 24 (2.0 g, 19.4 mmol) in a mixture
of AcOEt (20 ml) and tetrahydrofuran (THF) (10 ml), di-tert-butyl dicarbon-
ate (Boc2O) (4.23 g, 19.4 mmol) was added at room temperature. The mix-
ture was stirred for 14 h at room temperature. After evaporation of the sol-
vent, the concentrate was partitioned between AcOEt and saturated aqueous
NH4Cl. The organic layer was washed with brine, dried and evaporated in
vacuo to give 25 (4.17 g, 100%) as a colorless solid. Recrystallization was
1
was achieved from hexane–AcOEt. mp 203—204 °C. H-NMR (CDCl3) d:
2.64—2.72 (m, 2H), 2.76—2.82 (m, 4H), 2.98—3.06 (m, 2H), 3.22—3.28
(m, 4H), 7.02 (s, 1H), 7.28 (s, 1H), 9.00 (br s, 1H). IR (KBr) cmϪ1: 1716,
1522, 1377, 1333, 1281. FAB-MS m/z: 294 (MϩH)ϩ. Rf: 0.25 (hexane/
AcOEtϭ1/2). Anal. Calcd for C13H15N3O3S·0.2H2O: C, 52.58; H, 5.23; N,
14.15. Found: C, 52.76; H, 5.05; N, 14.02.
6-(4-Methylthiopiperidino)-7-nitro-3,4-dihydroquinolin-2(1H)-one
(23) A solution of 32 (300 mg, 1.30 mmol) in TFA (5 ml) was stirred at
0 °C for 0.5 h. The mixture was allowed to stand to come to room tempera-
ture, then stirred for 1 h. The reaction mixture was made basic with 2 M
NaOH at 0 °C, extracted with a mixture of CH2Cl2 and MeOH (5 : 1), dried
and evaporated in vacuo to give a yellow oil (163 mg). A solution of the oil
and 19 (70 mg, 0.308 mmol) in CH3CN (2 ml) was stirred at 90 °C for 2 h.
The reaction mixture was concentrated in vacuo. Preparative TLC (silica gel,
hexane/AcOEtϭ1/1) of the residue gave 23 (29 mg, 29%) as orange plates.
1
achieved from hexane–Et2O. mp 73—74 °C. H-NMR (CDCl3) d: 1.46 (s,
9H), 1.10—1.20 (m, 2H), 1.60—1.74 (m, 3H), 2.64—2.77 (m, 2H), 3.47—
3.53 (m, 2H), 4.06—4.20 (m, 2H). IR (KBr) cmϪ1: 3471, 2937, 1674. FAB-
MS m/z: 216 (MϩH)ϩ. Rf: 0.18 (hexane/AcOEtϭ1/1). Anal. Calcd for
C11H21NO3: C, 61.37; H, 9.83; N, 6.51. Found: C, 61.08; H, 10.09; N, 6.63.
1-tert-Butoxycarbonyl-4-formylpiperidine (26) To a solution of 25
(200 mg, 0.929 mmol) in CH2Cl2 (2 ml), Dess–Martin reagent13) (394 mg,
0.929 mmol) was added at room temperature, and the mixture was stirred for
1 h at room temperature. After evaporation of the solvent, the residue was
partitioned between AcOEt and 0.1 M NaOH. The organic layer was dried
and evaporated. Silica gel column chromatography (hexane/AcOEtϭ1/1) of
1
Recrystallization was achieved from hexane–AcOEt. mp 170—172 °C. H-
NMR (CDCl3) d: 1.75—1.87 (m, 2H), 2.02—2.09 (m, 2H), 2.13 (s, 3H),
2.62—2.77 (m, 3H), 2.80—2.89 (m, 2H), 2.96—3.03 (m, 2H), 3.20—3.28
(m, 2H), 6.99 (s, 1H), 7.28 (s, 1H), 8.45 (br s, 1H). IR (KBr) cmϪ1: 1678,
1522, 1379, 1333, 1284. FAB-MS m/z: 322 (MϩH)ϩ. Rf: 0.08 (hexane/
AcOEtϭ1/1). Anal. Calcd for C15H19N3O3S: C, 56.06; H, 5.96; N, 13.07.
Found: C, 55.92; H, 5.93; N, 13.21.
7-Nitro-6-piperidino-3,4-dihydroquinolin-2(1H)-one (22b) The title
compound was obtained as orange plates (27%), starting from piperidine
and following the method as described for 22a. Recrystallization was
1
the concentrate gave 26 (79 mg, 40%) as a colorless oil. H-NMR (CDCl3)
1
achieved from AcOEt. mp 202—203 °C. H-NMR (CDCl3) d: 1.54—1.62
d: 1.46 (s, 9H), 1.50—1.60 (m, 2H), 1.86—1.93 (m, 2H), 2.37—2.47 (m,
1H), 2.88—2.97 (m, 2H), 3.94—4.05 (m, 2H), 9.66 (s, 1H). IR (neat) cmϪ1
:
(m, 2H), 1.68—1.76 (m, 4H), 2.61—2.66 (m, 2H), 2.93—3.02 (m, 6H), 6.98
(s, 1H), 7.23 (s, 1H), 7.44 (br, 1H). IR (KBr) cmϪ1: 1684, 1522, 1379, 1343,
2976, 1728, 1685. FAB(Ϫ)-MS m/z: 212 (MϪH)Ϫ. HR-FAB-MS m/z