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S. Vangapandu et al. / Bioorg. Med. Chem. 12 (2004) 2501–2508
1H NMR spectra were recorded on 300 MHz Bruker
FT-NMR (Avance DPX300) spectrometer using tetra-
methylsilane as internal standard and the chemical shifts
are reported in d units. Mass spectra were recorded on
either GCMS (Shimadzu QP 5000 spectrometer) auto
sampler/direct injection (EI) or HRMS (Finnigan Mat
LCQ spectrometer) (APCI/ESI). Elemental analyses
were recorded on Elementar Vario EL spectrometer. All
chromatographic purification was performed with silica
gel 60 (230–400 mesh), whereas all TLC (silica gel)
development was performed on silica gel coated (Merck
Kiesel 60 F254, 0.2 mm thickness) sheets. All chemicals
were purchased from Aldrich Chemical Ltd (Milwau-
kee, WI, USA). Solvents used for the chemical synthesis
acquired from commercial sources were of analytical
grade, and were used without further purification unless
otherwise stated.
6.1.4. 2-Cyclohexyl-8-nitroquinoline (2d). Yield: 37%; mp
68–69 ꢁC; 1H NMR (CDCl3) d 8.14 (d, 1H, J ¼ 8:6 Hz),
7.97 (m, 2H), 7.53 (d, 1H, J ¼ 8:6 Hz), 7.34 (m, 1H),
3.74 (m, 1H), 1.97 (m, 10H); APCIMS m=z 257 (M+1).
Anal. Calcd for C15H16N2O2 (256.3): C, 70.29; H, 6.29;
N, 10.93. Found: C, 70.37; H, 6.35; N, 10.98.
6.1.5. 2,4-Diisopropyl-8-nitroquinoline (2e). Yield: 22%;
1
oil; H NMR (CDCl3) d 8.23 (d, 1H, J ¼ 8:5 Hz), 7.86
(d, 1H, J ¼ 8:5 Hz), 7.51 (m, 1H), 7.32 (s, 1H), 3.69 (m,
1H), 3.23 (m, 1H), 1.38 (m, 12H); EIMS m=z 258 (Mþ).
Anal. Calcd for C15H18N2O2 (258.3): C, 69.74; H, 7.02;
N, 10.84. Found: C, 69.99; H, 7.15; N, 10.88.
6.1.6. 2,4-Di-tert-butyl-8-nitroquinoline (2f). Yield: 20%;
1
oil; H NMR (CDCl3) d 8.21 (d, 1H, J ¼ 8:3 Hz), 7.81
(d, 1H, J ¼ 8:3 Hz), 7.47 (m, 1H), 7.30 (s, 1H), 1.42 (s,
9H), 1.40 (s, 9H); EIMS m=z 286 (Mþ). Anal. Calcd for
C17H22N2O2 (286.3): C, 71.30; H, 7.74; N, 9.78. Found:
C, 71.21; H, 7.68; N, 9.73.
6.1. General method for the synthesis of 2-substituted/2,4-
disubstituted-8-nitroquinolines (2a–h)
A solution of 8-nitroquinoline (1, 1 mmol) in CH3CN
(5 mL) was heated to 70–80 ꢁC. Silver nitrate (0.6 mmol),
requisite alkyl/cycloalkylcarboxylic acid (2.5 mmol), and
10% H2SO4 (15 mL) was added to the reaction mixture.
A freshly prepared solution of ammonium persulfate
(3 mmol) in water (10 mL) was added dropwise during
10 min. The heating source was removed and reaction
proceeded with the evolution of carbon dioxide. After
15 min, reaction mixture was poured onto ice, and made
alkaline by adding 25% NH4OH solution. Extracted
with CHCl3 (5 · 50 mL), and combined extracts were
washed with NaCl solution (2 · 15 mL). Dried over
Na2SO4, and solvent removed in vacuo to afford oil,
which upon column chromatography over silica gel
(230–400 mesh) afforded 2-substituted/2,4-disubstituted-
8-nitroquinolines (2a–h).
6.1.7. 2,4-Dicyclopentyl-8-nitroquinoline (2g). Yield:
1
21%; oil; H NMR (CDCl3) d 8.22 (d, 1H, J ¼ 8:4 Hz),
7.85 (d, 1H, J ¼ 8:4 Hz), 7.49 (m, 1H), 7.30 (s, 1H), 3.73
(m, 1H), 3.32 (m, 1H), 1.86 (m, 16H); EIMS m=z 310
(Mþ). Anal. Calcd for C19H22N2O2 (310.4): C, 73.52; H,
7.14; N, 9.03. Found: C, 73.58; H, 7.33; N, 9.17.
6.1.8. 2,4-Dicyclohexyl-8-nitroquinoline (2h). Yield: 20%;
1
oil; H NMR (CDCl3) d 8.20 (d, 1H, J ¼ 8:4 Hz), 7.78
(d, 1H, J ¼ 8:4 Hz), 7.44 (m, 1H), 7.20 (s, 1H), 3.26 (m,
1H), 2.85 (m, 1H), 1.57 (m, 20H); APCIMS m=z 339
(M+1). Anal. Calcd for C21H26N2O2 (338.4): C, 74.52;
H, 7.74; N, 8.28. Found: C, 74.69; H, 7.75; N, 8.30.
6.1.1. 2-Isopropyl-8-nitroquinoline (2a). Yield: 41%; mp
6.2. General method for the synthesis of ring-substituted-
8-quinolinamines (3a–c)
107–109 ꢁC; 1H NMR (CDCl3)
d 8.14 (d, 1H,
J ¼ 8:5 Hz), 7.94 (m, 2H), 7.48 (m, 2H), 3.23 (m, 1H),
1.36 (d, 6H, J ¼ 6:9 Hz); EIMS m=z 216 (Mþ). Anal.
Calcd for C12H12N2O2 (216.2): C, 66.65; H, 5.59; N,
12.96. Found: C, 66.68; H, 5.58; N, 12.88.
A solution of 8-nitroquinoline (2a, 2d, or 2h, 5 mmol) in
95% ethyl alcohol (20 mL) was hydrogenated over wet
raney-nickel (T1 grade) at 45 psi in a parr hydrogenator
for 45 min. Catalyst was removed by filtration, and fil-
trate was evaporated under vacuum to afford the re-
quired 8-quinolinamine as dark colored oil.
6.1.2. 2-tert-Butyl-8-nitroquinoline (2b). Yield: 45%; mp
104–105 ꢁC; 1H NMR (CDCl3)
d 8.14 (d, 1H,
J ¼ 8:7 Hz), 7.92 (m, 2H), 7.63 (d, 1H, J ¼ 8:7 Hz), 7.49
(m, 1H), 1.42 (s, 9H); EIMS m=z 230 (Mþ). Anal. Calcd
for C13H14N2O2 (230.3): C, 67.81; H, 6.13; N, 12.17.
Found: C, 67.88; H, 6.12; N, 12.33.
1
6.2.1. 8-Quinolinamine (3a). Yield: 95%; oil; H NMR
(CDCl3) d 8.76 (m, 1H), 8.10 (m, 1H), 7.36 (m, 2H), 7.14
(m, 1H), 7.93 (m, 1H), 4.90 (br s, 2H); EIMS m=z 144
(Mþ). Anal. Calcd for C9H8N2 (144.2): C, 74.98; H,
5.59; N, 19.43. Found: C, 75.21; H, 5.77; N, 19.07.
6.1.3. 2-Cyclopentyl-8-nitroquinoline (2c). Yield: 38%;
mp 76–78 ꢁC; 1H NMR (CDCl3) d 8.11 (d, 1H,
J ¼ 8:5 Hz), 7.93 (m, 2H), 7.50 (d, 1H, J ¼ 8:5 Hz), 7.44
(m, 1H), 3.78 (m, 1H), 1.88 (m, 8H); EIMS m=z 242
(Mþ). Anal. Calcd for C14H14N2O2 (242.3): C, 69.41; H,
5.82; N, 11.56. Found: C, 69.44; H, 5.87; N, 11.49.
6.2.2. 2-Cyclohexyl-8-quinolinamine (3b). Yield: 88%; oil;
1H NMR (CDCl3) d 8.05 (m, 1H), 7.54 (m, 2H), 7.42 (m,
1H), 7.09 (m, 1H), 4.76 (br s, 2H), 3.03 (m, 1H), 1.70 (m,
10H); EIMS m=z 226 (Mþ). Anal. Calcd for C15H18N2