Sodium hydride → 1-(t-Butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)prop-1-enyl)piperidine

HRID 1357946Notes

Reaction equation

HRID 1357946 reaction equation
[O:1]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.CCOCC>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=[CH:3][C:2](=[O:1])[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 1514430tert-Butyl 4-formylpiperidine-1-carboxylateHCID 18950746Dimethyl [2-oxo-2-(pyridin-3-yl)ethyl]phosphonate

Product 1

HCID 572456551-(t-Butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)prop-1-enyl)piperidineYield 80.5%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
45 °C

Procedure

A solution of dimethyl (2-oxo-2-(3-pyridyl)ethyl)phosphonate (150 mg, 0.65 mmol, from Procedure 38, Step A) in THF (1.8 mL) was added to a stirred suspension of sodium hydride (60% oil dispersion, 15 mg of sodium hydride, 0.63 mmol) in THF (3.0 mL). The resulting suspension was warmed in a 45° C. oil bath for 30 min. After the mixture had cooled to rt, 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde (112 mg, 0.53 mmol) was added in THF (1.5 mL). After stirring overnight at rt, the mixture was diluted with ether (20 mL) and washed with 2.5 N NaOH (20 mL) followed by saturated aq. brine (20 mL). The aq. layers were extracted in succession with ether (20 mL), and the combined organic layers were dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 80:20 v/v to 60:40 v/v hexanes/ethyl acetate, gave 135 mg of the title compound (trans isomer) as a yellow syrup. For the title compound: 1H NMR (500 MHz, CDCl3) δ9.17-9.13 (bs, 1H), 8.81 (bd, J=4, 1H), 8.27 (d, J=8, 1H), 7.49 (dd, J=8, 4, 1H), 7.07 (dd, J=15, 7, 1H), 6.85 (dd, J=15, 1, 1H), 4.25-4.13 (bs, 2H), 2.87-2.78 (m, 2H), 2.51-2.41 (m, 1H), 1.83 (d, J=12, 2H), 1.49 (s, 9H), 1.45 (qd, J=12, 4, 2H). ESI-MS 261 (M+H-56), 217 (M+H-100); HPLC A: 1.73 min.

Workup

  1. temperatureAfter the mixture had cooled to rt
  2. washwashed with 2.5 N NaOH (20 mL)
  3. extractionThe aq. layers were extracted in succession with ether (20 mL)
  4. dry with materialthe combined organic layers were dried (sodium sulfate)
  5. customdecanted
  6. customevaporated
  7. customPurification by flash column chromatography on silica gel
  8. washeluting with 80:20 v/v to 60:40 v/v hexanes/ethyl acetate

Sources & evidence

ORD record
ord-b853215a28df41609bafe6b970d13f20
Source dataset
uspto-grants-2003_07
Patent number
US06593346B2

Reaction notes

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