April 2014
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7-Chloro-2,3-dimethyl-1-propyl-1H-pyrrolo[2,3-c]pyridine (3H, m), 7.29–7.34 (1H, m), 7.78 (1H, d, J=5.4Hz). 13C-NMR
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(6c): Colorless crystals (89%). mp 72–73°C. H-NMR (CDCl3) (CDCl3) δ: 8.9, 10.3, 10.8, 19.1, 25.9, 43.8, 47.0, 105.5, 107.3,
δ: 0.97 (3H, t, J=6.9Hz), 1.71–1.83 (2H, m), 2.21 (3H, s), 2.37 112.5, 112.8, 116.9, 117.2, 120.4, 130.2, 130.3, 133.66, 133.70,
(3H, s), 4.35–4.41 (2H, m), 7.27 (1H, d, J=5.1Hz), 7.91 (1H, d, 133.8, 134.9, 135.9, 139.1, 139.2, 145.2, 160.4, 163.7. IR (ATR)
J=5.1 Hz).
7-Chloro-1-isobutyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine C, 73.82; H, 7.43; N, 12.91. Found: C, 73.76; H, 7.42; N, 12.55.
cm−1: 1607, 1554, 1496, 1471, 1367. Anal. Calcd for C20H24FN3:
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(6d): Colorless crystals (83%). mp 56–57°C. H-NMR (CDCl3)
N-(4-Fluoro-2-methylbenzyl)-1-isobutyl-2,3-dimethyl-1H-
δ: 0.90 (6H, d, J=6.6Hz), 2.21–2.30 (m, 1H), 2.45 (3H, d, pyrrolo[2,3-c]pyridine-7-amine (7e): Colorless solid (65%).
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J=0.9Hz), 4.23 (2H, brd, J=6.9Hz), 6.29 (1H, d, J=0.9Hz), mp 102–103°C. H-NMR (CDCl3) δ: 0.74 (6H, d, J=6.9Hz),
7.31 (1H, d, J=5.4Hz), 7.92 (1H, d, J=5.4 Hz).
Following compounds 2a and 7a–e were prepared in the 3.83 (2H, d, J=7.5Hz), 4.24 (1H, brt, J=4.5Hz), 4.64 (2H,
similar manner with compound 1.
2.01–2.10 (1H, m), 2.17 (3H, s), 2.27 (3H, s), 2.41 (3H, s),
d, J=4.5Hz), 6.83–6.94 (3H, m), 7.29–7.34 (1H, m), 7.78 (1H,
N-Benzyl-2,3-dimethyl-1-propyl-1H-pyrrolo[2,3-c]pyridine- d, J=5.7Hz). 13C-NMR (CDCl3) δ: 9.0, 10.9, 19.1, 19.6, 32.0,
7-amine (2a): Pale-yellow crystals (33%). mp 51–52°C. 43.9, 52.8, 105.4, 107.2, 112.5, 112.8, 116.9, 117.2, 120.6, 130.4,
1H-NMR (CDCl3) δ: 0.83 (3H, t, J=7.5Hz), 1.67–1.80 (2H, 130.5, 133.6, 133.7, 134.0, 135.4, 136.0, 139.2, 139.3, 145.3,
m), 2.17 (3H, s), 2.29 (3H, s), 4.04–4.09 (2H, m), 4.50 (1H, 160.5, 163.7. IR (ATR) cm−1: 1606, 1554, 1496, 1469, 1369.
br), 4.74 (2H, d, J=5.4Hz), 6.85 (1H, d, J=5.7Hz), 7.26–7.37 Anal. Calcd for C21H26FN3: C, 74.30; H, 7.72; N, 12.38. Found:
(3H, m), 7.41–7.45 (2H, m), 7.77 (1H, d, J=5.7Hz). 13C-NMR C, 74.13; H, 7.65; N, 12.19.
(CDCl3) δ: 8.9, 10.3, 10.9, 25.9, 46.5, 47.0, 105.5, 107.3, 120.6,
The following compounds 8, 9, and 10a were prepared in a
127.2, 127.9, 128.6, 133.9, 134.9, 135.9, 140.2, 145.3. IR (ATR) similar manner with compounds 4, 6, and 7, respectively.
cm−1: 1607, 1554, 1473, 1368. Anal. Calcd for C19H23N3: C,
77.78; H, 7.90; N, 14.32. Found: C, 77.69; H, 7.83; N, 14.43.
7-Chloro-2-methyl-1H-pyrrolo[2,3-c]pyridine (8): A pale-
yellow solid (28%). mp 160–161°C. H-NMR (CDCl3) δ: 2.52
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N-Benzyl-1,2,3-trimethyl-1H-pyrrolo[2,3-c]pyridine-7- (3H, s), 6.30 (1H, s), 7.34 (1H, d, J=5.6Hz), 7.98 (1H, d,
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amine (7a): Colorless solid (56%). mp 112–113°C. H-NMR J=5.6Hz), 8.46 (1H, br).
(CDCl3) δ: 2.17 (3H, s), 2.29 (3H, s), 3.90 (3H, s), 4.67 (1H,
7-Chloro-1-isobutyl-2-methyl-1H-pyrrolo[2,3-c]pyridine (9):
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brd, J=5.4Hz), 4.74 (2H, d, J=5.4Hz), 6.84 (1H, d, J=5.7Hz), An oil (81%). H-NMR (CDCl3) δ: 0.90 (6H, d, J=6.6Hz),
7.26–7.37 (3H, m), 7.42–7.57 (2H, m), 7.75 (1H, d, J=5.7Hz). 2.21–2.30 (1H, m), 2.45 (3H, d, J=0.9Hz), 4.23 (2H, brd,
13C-NMR (CDCl3) δ: 8.9, 10.3, 32.5, 46.4, 105.6, 107.1, 121.4, J=6.9Hz), 6.29 (1H, d, J=0.9Hz), 7.31 (1H, d, J=5.4Hz), 7.92
127.1, 127.9, 128.6, 133.5, 135.2, 135.9, 140.3, 145.8. IR (ATR) (1H, d, J=5.4 Hz).
cm−1: 1608, 1553, 1473, 1451, 1368. Anal. Calcd for C17H19N3:
N-(4-Fluoro-2-methylbenzyl)-1-isobutyl-2-methyl-1H-
C, 76.95; H, 7.22; N, 15.84. Found: C, 77.05; H, 7.28; N, 16.02. pyrrolo[2,3-c]pyridine-7-amine (10a): A colorless solid (88%).
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N-Benzyl-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyri- mp 132–133°C. H-NMR (CDCl3) δ: 0.76 (6H, d, J=6.9Hz),
dine-7-amine Hydrochloride (7b) The obtained free base 2.04–2.18 (1H, m), 2.36 (3H, d, J=0.9Hz), 2.42 (3H, s),
was dissolved in methanol (5mL), 10% hydrogen chloride 3.84 (2H, d, J=7.5Hz), 4.25 (1H, brt, J=4.8Hz), 4.65 (2H,
methanol solution (2mL) was added, and the mixture was d, J=4.8Hz), 6.16 (1H, d, J=0.9Hz), 6.85–6.96 (3H, m),
concentrated under reduced pressure. The residue was crystal- 7.31–7.35 (1H, m), 7.78 (1H, d, J=5.4 Hz).
lized from ethanol to give the title compound as a colorless
solid (24%). mp 232–235°C. H-NMR (DMSO-d6) δ: 1.24 (3H, yl-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (10b) 10a
7-[(4-Fluoro-2-methylbenzyl)amino]-1-isobutyl-2-meth-
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t, J=7.4Hz), 2.17 (3H, s), 2.42 (3H, s), 4.53 (2H, q, J=7.4Hz), (339mg, 1.0mmol) was dissolved in nitromethane (4mL)
4.89 (2H, d, J=6.2Hz), 7.10 (1H, d, J=7.0Hz), 7.28–7.46 (6H, and 1,2-dichloroethane (4mL), and aluminum(III) chloride
m), 8.00–8.20 (1H, m), 12.62 (1H, brs). 13C-NMR (DMSO-d6) (145mg, 1.1mmol) and dichloromethyl methyl ether (0.1mL,
δ: 8.3, 10.2, 17.0, 40.2, 44.8, 105.3, 109.6, 116.1, 124.5, 127.0, 1.1mmol) were added at 0°C. After stirring at the same tem-
127.3, 128.5, 134.2, 137.3, 141.0, 142.5. IR (ATR) cm−1: 1643, perature for 30min, the same amount of aluminum(III) chlo-
1603. ESI-HR-MS m/z: 280.1811 (Calcd for C18H21N3: 280.1808 ride and dichloromethyl methyl ether was added twice, and the
[M+H]+).
mixture was stirred for 1h. The reaction mixture was basified
1-Ethyl-N-(4-fluoro-2-methylbenzyl)-2,3-dimethyl-1H- with 8mol/L aqueous sodium hydroxide solution, and the mix-
pyrrolo[2,3-c]pyridine-7-amine (7c): Colorless solid (75%). mp ture was extracted with EtOAc. The extract was washed with
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102–104°C. H-NMR (CDCl3) δ: 1.29 (3H, t, J=7.2Hz), 2.18 saturated brine, dried over anhydrous sodium sulfate, and
(3H, s), 2.30 (3H, s), 2.41 (3H, s), 4.16 (2H, q, J=7.2Hz), 4.35 concentrated under reduced pressure. The residue was purified
(1H, brt, J=5.1Hz), 4.68 (2H, d, J=5.1Hz), 6.82–6.90 (3H, m), by silica gel column chromatography (eluent: hexane–EtOAc=
7.29–7.34 (1H, m), 7.78 (1H, d, J=5.4Hz). 13C-NMR (CDCl3) 1:1) to give the title compound as a colorless solid (259mg,
δ: 8.9, 10.0, 17.4, 19.2, 40.1, 43.7, 105.5, 107.6, 112.5, 112.7, 0.73mmol, 73%). mp 129–130°C. 1H-NMR (CDCl3) δ: 0.81
116.9, 117.2, 120.2, 130.0, 130.2, 133.65, 133.69, 133.9, 134.5, (6H, d, J=6.6Hz), 2.11–2.20 (1H, m), 2.41 (3H, s), 2.66 (3H, s),
135.9, 139.0, 139.1, 145.1, 160.4, 163.6. IR (ATR) cm−1: 1608, 3.90 (2H, d, J=6.9Hz), 4.26 (1H, br t, J=4.5Hz), 4.65 (2H, d,
1555, 1496, 1474, 1367. Anal. Calcd for C19H22FN3: C, 73.28; J=4.5Hz), 6.86–6.97 (2H, m), 7.30–7.34 (1H, m), 7.57 (1H, d,
H, 7.12; N, 13.49. Found: C, 73.06; H, 7.29; N, 13.48.
N-(4-Fluoro-2-methylbenzyl)-2,3-dimethyl-1-propyl-1H-
J=5.7Hz), 7.98 (1H, d, J=5.7Hz), 10.18 (1H, s).
{7-[(4-Fluoro-2-methylbenzyl)amino]-1-isobutyl-2-meth-
pyrrolo[2,3-c]pyridine-7-amine (7d): Colorless solid (33%). mp yl-1H-pyrrolo[2,3-c]pyridin-3-yl}methanol (10c) 10b (216
88–89°C. 1H-NMR (CDCl3) δ: 0.78 (3H, t, J=7.8Hz), 1.66–1.74 mg, 0.61mmol) was dissolved in methanol (5mL) and THF
(2H, m), 2.17 (3H, s), 2.29 (3H, s), 2.41 (3H, s), 3.99–4.04 (2H, (5mL), and sodium borohydride (41mg, 1.1mmol) was added
m), 4.28 (1H, brt, J=5.1Hz), 4.65 (2H, d, J=5.1Hz), 6.85–6.94 at 0°C. After stirring at room temperature for 1h, several