Bridged 5,6,7,8-Tetrahydro-1,6-naphthyridines, Analogues of Huperzine A
3-(Bromomethyl)-2-chloropyridine (4b): Yield 0.722 g, 85% (oil). IR
(61), 209 (72). HRMS: calcd. for C13H17ClN2O2 268.0979; found
1
(NaCl): ν = 2923 cm–1. H NMR (300 MHz, CDCl ): δ = 8.35 (d, 268.0989.
˜
3
J = 4.5 Hz, 1 H), 7.80 (d, J = 7.3 Hz, 1 H), 7.26 (dd, J = 7.3, J =
Methyl 1-[(2,5-Dichloro-3-pyridinyl)methyl]-3-piperidinecarboxylate
4.5 Hz, 1 H), 4.56 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
149.6, 148.1, 142.3, 134.1, 124.2, 28.5 ppm. MS (EI): m/z (%) = 170
(12), 126 (13). HRMS: calcd. for C6H5BrN 169.9005; found
169.9003 [M+ – Cl].
(3c): Yield 0.320 g, 53% (oil). IR (NaCl): ν = 2949, 2852, 2801,
˜
1
1734 cm–1. H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 2.0 Hz,
1 H), 7.87 (d, J = 2.0 Hz, 1 H), 3.70 (s, 3 H), 3.56 (s, 2 H), 2.81 (d,
J = 9.9 Hz, 1 H), 2.69–2.59 (m, 2 H), 2.50 (t, J = 10.1 Hz, 1 H),
3.31 (t, J = 8.5 Hz, 1 H), 1.92–1.86 (m, 1 H), 1.82–1.78 (m, 1 H),
1.68–1.58 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.6,
148.9, 146.7, 138.5, 135.0, 131.5, 59.0, 55.8, 54.5, 52.2, 42.9, 26.8,
24.7 (C-5Ј) ppm. MS (EI): m/z (%) = 302 (100), 287 (96), 271 (87).
HRMS: calcd. for C13H16Cl2N2O2 302.0589; found 302.0590.
3-(Bromomethyl)-2,5-dichloropyridine (4c): Yield 0.860 g, 72% (oil).
1
IR (NaCl): ν = 2920 cm–1. H NMR (300 MHz, CDCl ): δ = 8.31
˜
3
(d, J = 2.2 Hz, 1 H), 7.80 (d, J = 2.4 Hz, 1 H), 4.51 (s, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 149.0, 148.4, 139.5, 133.7, 131.6,
28.6 ppm. MS (EI): m/z (%) = 239 (7), 204 (6), 160 (100). HRMS:
calcd. for C6H4BrCl2N 238.8904; found 238.8904.
Methyl
1-[(2-Chloro-3-quinolinyl)methyl]-3-piperidinecarboxylate
(3d): Yield 0.445 g, 70% (oil). IR (NaCl): ν = 2950, 2852, 2804,
˜
3-(Bromomethyl)-2-chloroquinoline (4d): Yield 0.701 g, 55% (oil).
1
1733 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.74 (s, 1 H), 8.00 (d,
J = 8.3 Hz, 1 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.74 (t, J = 7.5 Hz, 1
H), 7.54 (t, J = 7.4 Hz, 1 H), 4.20 (s, 2 H), 3.67 (s, 3 H), 3.45–3.32
(m, 1 H), 3.27–3.16 (m, 1 H), 3.06–2.94 (m, 1 H), 2.78–2.68 (m, 1
H), 2.61–2.51 (m, 1 H), 2.15–2.03 (m, 1 H), 2.00–1.84 (m, 2 H),
1.63–1.50 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.2,
150.7, 147.3, 140.9, 131.0, 128.2, 128.0, 127.9, 127.4, 127.3, 58.2,
54.4, 53.2, 51.9, 40.5, 26.3, 23.4 ppm. MS (EI): m/z (%) = 318 (100),
303 (40), 287 (41), 259 (85). HRMS: calcd. for C17H19ClN2O2
318.1135; found 318.1131.
IR (NaCl): ν = 2919 cm–1. H NMR (300 MHz, CDCl ): δ = 8.44
˜
3
(s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.76
(td, J = 7.7, J = 1.4 Hz, 1 H), 7.62 (td, J = 7.5, J = 1.2 Hz, 1 H),
4.67 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.7, 146.3,
136.2, 134.2, 130.5, 128.2, 127.8, 127.6, 127.5, 60.2 ppm. MS (EI):
m/z (%) = 255 (51), 220 (63), 176 (90), 140 (100). HRMS: calcd.
for C10H7BrClN 254.9450; found 254.9466.
3-(Broommethyl)-2-chloro-6-methoxyquinoline (4e): Yield 0.741 g,
52% (oil). IR (NaCl): ν = 2919 cm–1. 1H NMR (300 MHz, CDCl ):
˜
3
δ = 8.13 (s, 1 H), 7.91 (d, J = 9.2 Hz, 1 H), 7.38 (dd, J = 9.2, J =
2.7 Hz, 1 H), 7.05 (d, J = 2.7 Hz, 1 H), 4.70 (s, 2 H), 3.3 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 158.9, 147.7, 143.8, 138.5,
130.1, 130.0, 128.7, 124.2, 105.4, 56.1, 30.3 ppm. MS (EI): m/z (%)
= 285 (14), 206 (100). HRMS: calcd. for C11H9BrClNO 284.9556;
found 284.9567.
Methyl 1-[(2-Chloro-6-methoxy-3-quinolinyl)methyl]-3-piperidine-
carboxylate (3e): Yield 0.473 g, 68% (oil). IR (NaCl): ν = 2950,
˜
1
2850, 2803, 1732 cm–1. H NMR (400 MHz, CDCl3): δ = 8.13 (s,
1 H), 7.89 (d, J = 9.0 Hz, 1 H), 7.33 (dd, J = 9.0, J = 2.7 Hz, 1
H), 7.08 (d, J = 2.7 Hz, 1 H), 3.93 (s, 3 H), 3.71 (s, 2 H), 3.67 (s,
3 H), 2.99 (d, J = 10.8 Hz, 1 H), 2.83–2.78 (m, 1 H), 2.71–2.64 (m,
1 H), 2.47 (t, J = 10.1 Hz, 1 H), 2.30 (t, J = 9.5 Hz, 1 H), 2.00–
1.93 (m, 1 H), 1.84–1.78 (m, 1 H), 1.72–1.60 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 174.9, 158.5, 148.8, 143.1, 137.1,
131.0, 129.6, 128.9, 122.9, 105.4, 59.7, 56.0, 55.9, 54.4, 52.0, 42.2,
27.1, 24.9 ppm. MS (EI): m/z (%) = 348 (100), 289 (33). HRMS:
calcd. for C18H21ClN2O3 348.1241; found 348.1239.
3. Synthesis of Ring-Closing Precursors 3a–e
General Procedure: Methyl 3-piperidinecarboxylate (430 mg,
3 mmol) and K2CO3 (274 mg, 2 mmol) were added to a solution of
3-(bromomethyl)pyridine 4a–e (2 mmol) in MeOH (50 mL). The
reaction mixture was stirred at 75 °C for 1 h and then cooled to
room temp. Following the addition of water (30 mL), the mixture
was extracted with CH2Cl2 (3ϫ50 mL). The organic layers were
dried with MgSO4, and the solvent was removed under reduced
pressure. The residue was purified by column chromatography (sil-
ica gel, eluent heptane/EtOAc, 90:10).
4. Synthesis of Bridged Compounds 1a–e
General Procedure: KN(SiMe3)2 (0.5 solution in toluene, 1.2 mL,
0.6 mmol) was added to a solution of ring-closing precursor 3a–e
(0.5 mmol) in dried toluene (5 mL). The reaction mixture was
stirred at 80 °C for 30 min and then cooled to room temp. Follow-
ing the addition of a saturated NH4Cl solution (10 mL), the mix-
ture was extracted with CH2Cl2 (3ϫ10 mL). The organic layers
were dried with MgSO4, and the solvent was removed under re-
duced pressure. The residue was purified by reversed phase HPLC
(gradient of MeOH and H2O with 0.1% formic acid).
Methyl 1-[(2,6-Dichloro-5-methyl-3-pyridinyl)methyl]-3-piperidine-
carboxylate (3a): Yield 0.537 g, 85% (oil). IR (NaCl): ν = 2950,
˜
1
2855, 2805, 1734 cm–1. H NMR (400 MHz, CDCl3): δ = 7.69 (s,
1 H), 3.65 (s, 3 H), 3.51 (s, 2 H), 2.82 (d, J = 10.2 Hz, 1 H), 2.68–
2.62 (m, 1 H), 2.60–2.54 (m, 1 H), 2.38 (t, J = 10.2 Hz, 1 H), 2.33
(s, 3 H), 2.24–2.16 (m, 1 H), 1.90–1.82 (m, 1 H), 1.76–1.68 (m, 1
H), 1.60–1.48 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
174.3, 148.2, 146.6, 141.9, 131.7, 131.4, 58.2, 55.3, 53.9, 51.7, 41.6,
26.5, 24.4, 18.9 ppm. MS (EI): m/z (%) = 316 (100), 301 49), 285
(50), 257 (73). HRMS: calcd. for C14H19Cl2N2O2 316.0745; found
316.0753.
1
1a: Yield 0.042 g, 30% (oil). IR (NaCl): ν = 2925, 1653 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 7.21 (s, 1 H), 4.36 (d, J = 17.2 Hz,
1 H), 3.74 (d, J = 17.2 Hz, 1 H), 3.71 (s, 3 H), 3.43 (d, J = 13.0 Hz,
1 H), 3.21 (d, J = 13.0 Hz, 1 H), 3.03–2.95 (m, 2 H), 2.31 (s, 3 H),
2.15–2.10 (m, 2 H), 1.44–1.38 (m, 1HЈ), 1.18–1.10 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.9, 153.6, 149.2, 135.7, 130.8,
130.8, 55.0, 54.6, 53.3, 52.2, 46.0, 31.6, 19.4, 19.4 ppm. MS (EI):
m/z (%) = 280 (72), 221 (100). HRMS: calcd. for C14H17ClN2O2
280.0979; found 280.0973.
Methyl
1-[(2-Chloro-3-pyridinyl)methyl]-3-piperidinecarboxylate
(3b): Yield 0.322 g, 60% (oil). IR (NaCl): ν = 2949, 2854, 2803,
˜
1
1734 cm–1. H NMR (400 MHz, CDCl3): δ = 8.28 (dd, J = 4.6, J
= 1.6 Hz, 1 H), 7.85 (d, J = 7.7 Hz, 1 H), 7.24 (dd, J = 7.7, J =
4.6 Hz, 1 H), 3.67 (s, 3 H), 3.60 (s, 2 H), 2.89 (d, J = 10.6 Hz, 1
H), 2.73–2.67 (m, 1 H), 2.65–2.58 (m, 1 H), 2.42 (t, J = 10.0 Hz, 1
1b: Yield 0.032 g, 28% (oil). IR (NaCl): ν = 2950, 2938, 1647 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 4.6 Hz, 1 H), 7.43
H), 2.28–2.22 (t, J = 9.8 Hz, 1 H), 1.95–1.88 (m, 1 H), 1.80–1.73 (d, J = 7.6 Hz, 1 H), 7.19 (dd, J = 7.6, J = 4.6 Hz, 1 H), 4.57 (d,
(m, 1 H), 1.65–1.52 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): J = 17.6 Hz, 1 H), 3.87 (d, J = 17.6 Hz, 1 H), 3.78 (s, 3 H), 3.61
δ = 174.7, 151.3, 148.2, 139.2, 133.5, 122.9, 59.3, 55.8, 54.3, 52.0,
(d, J = 13.0 Hz, 1 H), 3.31 (d, J = 13.0 Hz, 1 H), 3.12–3.08 (m, 2
42.1, 26.9, 24.8 ppm. MS (EI): m/z (%) = 268 (100), 253 (63), 137 H), 2.24–2.20 (m, 1 H), 2.16 (td, J = 13.4, J = 4.2 Hz, 1 H), 1.60–
Eur. J. Org. Chem. 2009, 643–654
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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