August 2002
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m/z: 183.1281 (Calcd for C10H17NO2 183.1259).
added and the mixture was then refluxed with Dean–Stark for
1-Benzoylpiperidin-4-one, 9c As described for the 24 h. The reaction mixture was concentrated in vacuo. The
preparation of 9a, the amide 8c (2.23 g, 9.02 mmol) was de- residue was dissolved in EtOH (6 ml), NaBH4 (0.24 g,
protected with 5% HCl (5 ml) in MeOH (5 ml) for 50 h, and 6.34 mmol) was slowly added and stirred at room tempera-
purified by silica gel column chromatography (ethyl acetate): ture for 1 h. Then it was evaporated, water (5 ml) and CH2Cl2
1
pale yellow oil, yield 1.83 g (99%); H-NMR (DMSO-d6, (20 ml) were added, the suspension was filtered, and the fil-
80 °C) d: 2.34 (2H, dd, Jϭ6.2, 6.2 Hz), 3.65 (2H, dd, Jϭ6.2, trate was washed with a saturated solution of NaOH and
6.2 Hz), 7.26—7.37 (5H, aromatic). 13C-NMR (CDCl3) d: NaCl, dried (Na2SO4), and concentrated in vacuo. The
41.1, 64.4, 106.8, 126.8, 128.6, 130.1, 135.0, 170.8, 206.6. residue was purified by silica gel column chromatography
HR-MS m/z: 203.0916 (Calcd for C12H13NO2 203.0946).
(CH2Cl2/MeOH/NH4OHaq 90 : 9 : 1), to give 4a as colorless
1-(4-Dimethylaminopiperidin-1-yl)ethanone, 3a To a oil (1.37 g, 85%). 1H-NMR (CDCl3) d: 0.93 (3H, t,
solution of the ketone 9a (1.08 g, 7.65 mmol) in EtOH Jϭ7.3 Hz), 1.22—1.48 (10H, m), 1.71—1.80 (2H, m), 2.09
(13 ml) was successively added dimethylamine hydrochloride (3H, m), 2.41 (4H, dd, Jϭ7.3, 7.3 Hz), 2.48 (1H, ddd,
(1.35 g, 16.55 mmol), 3 Å molecular sieves, and NaBH3CN Jϭ12.9, 12.9, 2.6 Hz), 2.68 (1H, dddd, Jϭ11.5, 11.5, 3.6,
(0.80 g, 12.73 mmol). To the reaction mixture HCl/EtOH was 3.6 Hz), 3.00 (1H, ddd, Jϭ13.0, 13.0, 2.6 Hz), 3.85 (1H, dm,
added until pH 6 and stirred for 96 h at room temperature. Jϭ13.3 Hz), 4.67 (1H, dm, Jϭ13.2 Hz). 13C-NMR (CDCl3)
Then it was evaporated, water (5 ml) and CH2Cl2 (10 ml) d: 13.9, 20.4, 21.3, 27.7, 28.9, 31.1, 41.4, 46.2, 50.1, 58.2,
were added, the suspension was filtered, and the filtrate was 168.5. HR-MS m/z: 254.2380 (Calcd for C15H30N2O
washed with a saturated solution of NaOH and NaCl, dried 254.2358).
(Na2SO4), and concentrated in vacuo. The residue was puri-
1-(4-Dibutylaminopiperidin-1-yl)pentan-1-one, 4b As
fied by silica gel column chromatography (CH2Cl2/MeOH/ described for the preparation of 4a, the ketone 9b (0.80 g,
NH4OHaq 70 : 9 : 1), to give 3a as colorless oil (0.69 g, 53%). 4.37 mmol) was reductively aminated with dibutylamine
1H-NMR (CDCl3) d: 1.34 (2H, dddd, Jϭ12.0, 12.0, 11.2, (0.69 g, 5.34 mmol), NaBH4 (0.17 g, 4.49 mmol), and purified
4.3 Hz), 1.76—1.85 (2H, m), 2.04 (3H, s), 2.23 (6H, s), 2.29 by silica gel column chromatography (CH2Cl2/MeOH/
1
(1H, dddd, Jϭ11.2, 11.2, 3.7, 3.7 Hz ), 2.53 (1H, ddd, NH4OHaq 140 : 9 : 1): colorless oil, yield 1.01 g (78%); H-
Jϭ12.0, 12.0, 2.3 Hz), 3.00 (1H, ddd, Jϭ12.0, 12.0, 2.2 Hz), NMR (CDCl3) d: 0.92 (9H, dt, Jϭ6.9, 7.0 Hz), 1.22—1.46
3.79 (1H, ddm, Jϭ13.5, 2.6 Hz), 4.57 (1H, ddm, Jϭ13.3, (12H, m), 1.55—1.67 (2H, m), 1.70—1.81 (2H, m), 2.33
1.4 Hz). 13C-NMR (CDCl3) d: 21.3, 27.7, 29.0, 40.7, 41.5, (2H, dd, Jϭ7.7, 7.7 Hz), 2.41 (4H, dd, Jϭ7.3, 7.3 Hz), 2.47
45.5, 61.9, 168.6. HR-MS m/z: 170.1374 (Calcd for (1H, ddd, Jϭ12.8, 12.8, 2.6 Hz), 2.68 (1H, dddd, Jϭ11.5,
C9H18N2O 170.1419).
11.5, 3.6, 3.6 Hz), 2.97 (1H, ddd, Jϭ13.0, 13.0, 2.2 Hz), 3.89
1-(4-Dimethylaminopiperidin-1-yl)pentan-1-one, 3b (1H, dm, Jϭ11.2 Hz), 4.67 (1H, dm, Jϭ11.2 Hz). 13C-NMR
As described for the preparation of 3a, the ketone 9b (0.66 g, (CDCl3) d: 13.6, 13.7, 13.8, 20.2, 20.3, 22.2, 22.3, 27.2,
3.60 mmol) was reductively aminated with dimethylamine 27.3, 27.7, 28.9, 30.9, 32.8, 41.3, 45.3, 29.9, 58.1, 171.0.
hydrochloride (0.73 g, 9.00 mmol), NaBH3CN (0.23 g, 3.66 HR-MS m/z: 296.2827 (Calcd for C18H36N2O 296.2828).
mmol), and purified by silica gel column chromatography
(4-Dibutylaminopiperidin-1-yl)phenylmethanone, 4c
(CH2Cl2/MeOH/NH4OHaq 90 : 9 : 1): colorless oil, yield As described for the preparation of 4a, the ketone 9c (0.87 g,
1
425 mg (56%); H-NMR (CDCl3) d: 0.93 (3H, t, Jϭ7.4 Hz), 4.28 mmol) was reductively aminated with dibutylamine
1.30—1.43 (4H, m), 1.55—1.66 (2H, m), 1.74—1.90 (4H, (0.67 g, 5.18 mmol), NaBH4 (0.17 g, 4.49 mmol), and purified
m), 2.28 (6H, s), 2.30—2.40 (3H, m), 2.56 (1H, ddd, Jϭ12.8, by silica gel column chromatography (CH2Cl2/MeOH/
1
12.8, 2.6 Hz), 3.01 (1H, ddd, Jϭ12.9, 12.9, 2.6 Hz), 3.90 NH4OHaq 140 : 9 : 1): colorless oil, yield 0.79 g (58%); H-
(1H, dm, Jϭ13.5 Hz), 4.64 (1H, dm, Jϭ13.9 Hz). 13C-NMR NMR (DMSO-d6, 80 °C) d: 0.78 (6H, t, Jϭ7.1 Hz), 1.12—
(CDCl3) d: 13.7, 22.4, 27.4, 27.9, 29.1, 33.0, 40.7, 41.5, 1.34 (10H, m), 1.57 (2H, dm, Jϭ12.5 Hz), 2.33 (4H, t,
44.8, 62.0, 171.3. HR-MS m/z: 212.1915 (Calcd for Jϭ6.9 Hz), 2.61 (1H, dddd, Jϭ11.3, 11.3, 3.6, 3.6 Hz), 2.76
C12H24N2O 212.1889).
(1H, dd, Jϭ12.0, 12.0 Hz), 3.95 (2H, Br), 7.23—7.36 (5H,
(4-Dimethylaminopiperidin-1-yl)phenylmethanone, 3c aromatic). 13C-NMR (CDCl3) d: 13.9, 14.0, 20.4, 20.4, 28.0,
As described for the preparation of 3a, the ketone 9c (1.96 g, 28.9, 30.9, 50.1, 50.2, 58.2, 58.3, 126.7, 128.2, 129.3, 136.1,
9.64 mmol) was reductively aminated with dimethylamine 170.0. HR-MS m/z: 316.2532 (Calcd for C20H32N2O
hydrochloride (1.96 g, 24.00 mmol), NaBH3CN (0.61 g, 9.71 316.2515).
mmol), and purified by silica gel column chromatography
(4-Dimethylaminopiperidin-1-yl)ethane, 5a To a solu-
(CH2Cl2/MeOH/NH4OHaq 90 : 9 : 1): colorless oil, yield tion of lithium aluminum hydride (LiAlH4) (0.23 g, 6.06
1
1.00 g (45%); H-NMR (DMSO-d6, 80 °C) d: 1.17—1.32 mmol) in THF (3 ml) was added the solution of 3a (676 mg,
(2H, m), 1.65 (2H, dm, 14.3 Hz), 2.09 (3H, m), 2.24 (1H, 3.97 mmol) in THF (2 ml), and then refluxed under nitrogen
dddd, Jϭ10.7, 10.7, 3.8, 3.8 Hz), 2.82 (1H, ddd, Jϭ11.1, atmosphere for 2 h. The reaction mixture was quenched with
11.1, 2.8 Hz), 3.89 (1H, Br), 7.22—7.37 (5H, aromatic). 13C- water, and the solvent was evaporated. The residue was dis-
NMR (CDCl3) d: 41.6, 61.9, 126.6, 128.3, 129.4, 136.0, solved in CH2Cl2, washed with saturated K2CO3 and brine,
170.0. HR-MS m/z: 232.1605 (Calcd for C14H20N2O dried over Na2SO4, and the solvent was evaporated. The
232.1575).
residue was purified by silica gel column chromatography
1-(4-Dibutylaminopiperidin-1-yl)ethanone, 4a To a (CH2Cl2/MeOH/NH4OHaq 50 : 9 : 1) to give 5a as colorless
solution of the ketone 9a (0.90 g, 6.34 mmol), dibutylamine oil (456 mg, 74%). 1H-NMR (CDCl3) d: 1.08 (3H, t,
(0.98 g, 7.58 mmol) and p-toluenesulfonic acid monohydrate Jϭ7.2 Hz), 1.52 (1H, ddd, Jϭ11.9, 11.3, 3.6 Hz), 1.57 (1H,
(TsOH·H2O) (0.12 g, 0.63 mmol) in benzene (10 ml) was ddd, Jϭ11.9, 11.3, 2.4 Hz), 1.77—1.93 (4H, m), 2.15 (1H,