3746
S. Nsumiwa et al. / Bioorg. Med. Chem. 21 (2013) 3738–3748
The crude products were obtained after base extraction into CHCl3
and were purified by preparative HPLC.
Full synthetic details for previously reported compounds are
provided as Supplementary data, while details for novel com-
pounds are provided below.
5.1.5. 4-(Methylamino)quinolin-7-carbonitrile (10e)
Compound 7e and excess methylamine (33% in MeOH) were
heated in a sealed tube at 90 °C for 6 h. The mixture was allowed
to cool to room temperature and concentrated under reduced pres-
sure. The product was then purified by silica gel chromatography
using MeOH:EtOAc:Et3N (1:98:1) and obtained as a white solid
(90 mg, 65%), mp 252–254 °C. NMR—dH (400 MHz; DMSO) 2.87
(3H, d, J 4.7 Hz, NHCH3), 6.47 (1H, d, J 5.4 Hz, H-3), 7.51 (1H, d, J
4.4 Hz, NHCH3), 7.68 (1H, dd, J 1.7, 8.7 Hz, H-6), 8.22 (1H, d, J
1.7 Hz, H-8), 8.28 (1H, d, J 8.7 Hz, H-5), 8.48 (1H, d, J 5.4 Hz, H-2).
dC (100 MHz; DMSO) 29.8 (NHCH3), 100.3 (C-7), 111.9 (Ar-CN),
119.2 (C-3), 121.8 (C-5), 124.0 (C-4a), 125.0 (C-6), 135.0 (C-8),
147.7 (C-8a), 151.2 (C-2), 153.0 (C-4). HPLC tR = 9.51 min, purity
P98%. HRMS (ESI) m/z 184.0874 (C11H9N3, [M+H]+ requires
184.0796).
5.1.1. 4-Aminoquinolin-7-carboxamide (9d)
Compound 7d was heated in a sealed tube with excess aqueous
ammonia at 70 °C for 4 h. The mixture was cooled to room temper-
ature and the solid filtered. Solid was then washed with 5% NH3
(aq) and dried. Following silica gel chromatography and prepara-
tive HPLC where purity was above 98% the product was obtained
as
a white solid (50 mg, 40%). mp 132–134 °C. NMR—dH
(400 MHz; DMSO) 5.12 (2H, br s, –NH2), 6.66 (1H, d, J 5.1 Hz, H-
3), 7.80 (1H, d, J 8.8 Hz, H-6), 8.34 (1H, d, J 8.8 Hz, H-5), 8.42 (1H,
s, H-8), 8.56 (1H, d, J 5.1 Hz, H-2). dC (100 MHz; DMSO) 116.8 (C-
3), 121.8 (C-4a), 124.9 (C-5), 125.3 (C-6), 126.8 (C-8), 127.7 (C-7),
143.1 (C-8a), 153.2 (C-2), 153.6 (C-4), 156.3 (–CONH2). HPLC
tR = 9.51 min, purity P98%. HRMS (ESI) m/z 187.1980 (C10H9N3O,
M+ requires 187.1969).
5.1.6. N-Methyl-7-nitroquinolin-4-amine (10h)
Compound 7h and excess methylamine (33% in MeOH) were
heated in a sealed tube at 90 °C for 6 h. The mixture was allowed
to cool to room temperature and concentrated under reduced pres-
sure. The product was then purified by silica gel chromatography
using MeOH:EtOAc:Et3N (1:98:1) and obtained as a yellow solid
(40 mg, 55%), mp >330 °C. NMR—dH (400 MHz; DMSO) 2.94 (3H,
s, NHCH3), 6.55 (1H, d, J 5.3 Hz, H-3), 8.10 (1H, dd, J 2.0, 9.2 Hz,
H-6), 8.48 (1H, d, J 9.2 Hz, H-5), 8.54 (1H, d, J 1.8 Hz, H-8), 8.57
(1H, d, J 5.3 Hz, H-2). dC (100 MHz; DMSO) 31.1 (CH3), 102.7 (C-
3), 110.5 (C-8), 123.0 (C-6), 128.0 (C-5), 135.0 (C-4a), 147.3 (C-
8a), 149.6 (C-3), 149.8 (C-7), 151.9 (C-4). HPLC tR = 5.30 min, purity
P98%. HRMS (ESI) m/z 204.0792 (C10H9N3O2, [M+H]+ requires
204.0773).
5.1.2. N,7-Dimethylquinolin-4-amine (10a)
Compound 7a and excess methylamine (33% in MeOH) were
heated in a sealed tube at 90 °C for 6 h. The mixture was allowed
to cool to room temperature and concentrated under reduced pres-
sure. The product was then purified by silica gel chromatography
using MeOH:EtOAc:Et3N (1:98:1) and obtained as a white solid
(80 mg, 65%), mp 133–135 °C. NMR—dH (400 MHz; DMSO) 2.51
(3H, s, Ar-CH3), 3.07 (3H, d, J 4.6 Hz, NHCH3), 6.66 (1H, d, J
7.0 Hz, H-3), 7.49 (1H, dd, J 1.5, 8.7 Hz, H-6), 7.75 (1H, br s, H-8),
8.43 (1H, d, J 6.9 Hz, H-2), 8.45 (1H, d, J 8.7 Hz, H-5), 9.34 (1H, br
s, NHCH3). dC (100 MHz; DMSO) 20.9 (Ar-CH3), 29.1 (–NHCH3),
97.2 (C-3), 116.4 (C-4a), 121.4 (C-5), 125.7 (C-6), 127.1 (C-8),
138.4 (C-7), 147.3 (C-8a), 149.8 (C-3), 151.1 (C-4). HPLC
tR = 10.60 min, purity P98%. HRMS (ESI) m/z 173.1062 (C11H12N2,
[M+H]+ requires 173.1079).
5.1.7. 7-Methoxy-N-methylquinolin-4-amine (10i)
Compound 7i and excess methylamine (33% in MeOH) were
heated in a sealed tube at 90 °C for 6 h. The mixture was allowed
to cool to room temperature and concentrated under reduced pres-
sure. The product was then purified by silica gel chromatography
using MeOH:EtOAc:Et3N (1:98:1) and obtained as a white solid
(100 mg, 60%), mp 75–78 °C. NMR—dH (400 MHz; DMSO) 2.94
(3H, br s, –NHCH3), 3.85 (3H, s, Ar-OCH3), 6.44 (1H, d, J 6.4 Hz, H-
3), 7.13 (1H, dd, J 2.6, 9.2 Hz, H-6), 7.25 (1H, d, J 2.6 Hz, H-8),
8.22 (1H, d, J 9.3 Hz, H-5), 8.26 (1H, s, Ar-NHCH3), 8.33 (1H, d, J
6.4 Hz, H-2). dC (100 MHz; DMSO) 30.0 (–NHCH3), 56.1 (Ar-OCH3),
103.7 (C-8), 112.3 (C-3), 117.1 (C-4a), 124.5 (C-6), 144.3 (C-5),
146.0 (C-8a), 154.3 (C-2), 161.8 (C-4), 164.8 (C-7). HPLC
tR = 8.91 min, purity P98%. HRMS (ESI) m/z 189.1026
(C11H12N2O, [M+H]+ requires 189.1028).
5.1.3. N-Methyl-7-(triflouromethyl)quinolin-4-amine (10b)
Compound 7b and excess methylamine (33% in MeOH) were
heated in a sealed tube at 90 °C for 6 h. The mixture was allowed
to cool to room temperature and concentrated under reduced pres-
sure. The product was then purified by silica gel chromatography
using MeOH:EtOAc:Et3N (1:98:1) and obtained as a white solid
(70 mg, 60%), mp 227–229 °C. NMR—dH (400 MHz; DMSO) 2.87
(3H, d, J 4.7 Hz, NHCH3), 6.47 (1H, d, J 5.4 Hz, H-3), 7.51 (1H, d, J
4.3 Hz, NHCH3), 7.64 (1H, dd, J 1.9, 8.8 Hz, H-6), 8.04 (1H, br s, H-
8), 8.34 (1H, d, J 8.8 Hz, 5), 8.48 (1H, d, J 5.3 Hz, H-2). dC
(100 MHz; DMSO) 29.8 (NHCH3), 100.0 (C-3), 119.4 (C-6), 121.3
(C-5), 124.1 (C-4a), 126.8 (Ar-CF3), 126.8 (C-8), 129.4 (C-7), 147.9
(C-8a), 151.3 (C-2), 152.8 (C-4). HPLC tR = 9.49 min, purity P98%.
HRMS (ESI) m/z 227.0782 (C11H9F3N2, [M+H]+ requires 227.0796).
5.1.8. N4-Methylquinolin-4,7-diamine (10g)
Stannous chloride (SnCl2) (0.87 g, 4.57 mmol) dissolved in con-
centrated HCl (3 mL) was added slowly to a stirred solution of 10h
(0.12 g, 0.57 mmol) in glacial acetic acid (20 mL). The mixture was
stirred at 60 °C for 2 h. After the mixture was cooled, acetone
(50 mL) was added and it was stirred vigorously. Precipitate was
collected by filtration, washed with acetone, and suspended in
water (250 mL). The suspension was made basic (pH 12) with so-
dium hydroxide and the product was extracted with chloroform
(5 ꢁ 50 mL). The crude product was purified by silica gel chroma-
tography with chloroform–methanol (10:1) containing 0.5% trieth-
ylamine. Solvent was evaporated to obtain 10g (84 mg, 70%) as a
yellow solid mp 283–285 °C. NMR—dH (400 MHz; DMSO) 2.91
(3H, d, J 4.7 Hz, –NHCH3), 6.53 (1H, d, J 5.4 Hz, H-3), 7.45 (1H, bs,
–NHCH3), 8.08 (1H, dd, J 2.3, 9.2 Hz, H-6), 8.36 (1H, d, J 9.2 Hz, H-
5), 8.52 (1H, d, J 2.3 Hz, H-8), 8.54 (1H, d, J 5.3 Hz, H-2). dC
(100 MHz; DMSO) 29.8 (–NHCH3), 100.7 (C-3), 117.1 (C-8), 123.1
(C-4a), 124.5 (C-5), 124.9 (C-6), 148.0 (C-7), 150.3 (C-8a), 151.5
5.1.4. 4-(Methylamino)quinolin-7-carboxamide (10d)
Compound 7d and excess methylamine (33% in MeOH) were
heated in a sealed tube at 90 °C for 6 h. The mixture was allowed
to cool to room temperature and concentrated under reduced pres-
sure. The product was then purified by silica gel chromatography
using MeOH:EtOAc:Et3N (1:98:1) and obtained as a white solid
(60 mg, 50%), mp 165–166 °C. NMR—dH (400 MHz; DMSO) 2.82
(1H, d, J 4.6 Hz, NHCH3), 5.88 (1H, d, J 3.9 Hz, NHCH3), 6.68 (1H,
d, J 5.5 Hz, H-3), 7.69 (1H, d, J 8.4 Hz, H-5), 7.91 (1H, d, J 0.8 Hz,
H-8), 8.06 (1H, dd, J 1.3, 8.5 Hz, H-6), 8.52 (1H, d, J 5.4 Hz, H-2).
dC (100 MHz; DMSO) 31.1 (NHCH3), 102.7 (C-3), 110.4 (C-4a),
123.0 (C-5), 128.0 (C-6), 135.0 (C-8), 147.3 (C-7), 149.6 (C-8a),
149.8 (C-2), 151.9 (C-4). HPLC tR = 9.58 min, purity P98%. HRMS
(ESI) m/z 201.0700 (C11H11N3O, M+ requires 201.0902).