Sodium hydride → Tert-butyl 4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate

HRID 717876Notes

Reaction equation

HRID 717876 reaction equation
[H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=1>O1CCCC1>[F:25][C:24]([F:27])([F:26])[C:20]1[N:19]=[C:18]([O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH:23]=[CH:22][CH:21]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 6023342-Chloro-6-(trifluoromethyl)pyridineHCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylate

Product 1

HCID 86706857Tert-butyl 4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a mixture of sodium hydride (0.88 g, 60% in mineral oil, 22 mmol) in tetrahydrofuran (50. mL) at 0° C. was added tert-butyl 4-hydroxypiperidine-1-carboxylate (4.4 g, 22 mmol, Aldrich). The mixture was stirred at room temperature for one hour. A solution of 2-chloro-6-(trifluoromethyl)pyridine (2.0 g, 11 mmol, Oakwood) in tetrahydrofuran (10 mL) was added. The mixture was stirred at room temperature for 2 days. The mixture was quenched by the addition of water, and the product was extracted with EtOAc. The extract was washed with water, followed by brine, was dried over sodium sulfate, filtered and concentrated. Flash chromatography on a 120 g silica gel cartridge, eluting with a gradient from 0-15% EtOAc in hexanes afforded product as a colorless oil (3.8 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.75-7.64 (m, 1H), 7.23 (d, J=7.3 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 5.27 (tt, J=7.7, 3.7 Hz, 1H), 3.83-3.66 (m, 2H), 3.31 (ddd, J=13.4, 8.5, 3.7 Hz, 2H), 1.99 (ddt, J=13.3, 6.9, 3.7 Hz, 2H), 1.73 (dtd, J=12.3, 8.1, 3.9 Hz, 2H), 1.47 (s, 9H). 19F NMR (376 MHz, CDCl3) δ −68.94 (s). LCMS (M-tBu+H)+: 291.0.

Workup

  1. stirringThe mixture was stirred at room temperature for 2 days
  2. customThe mixture was quenched by the addition of water
  3. extractionthe product was extracted with EtOAc
  4. washThe extract was washed with water
  5. dry with materialwas dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. washFlash chromatography on a 120 g silica gel cartridge, eluting with a gradient from 0-15% EtOAc in hexanes afforded product as a colorless oil (3.8 g, 100%)

Sources & evidence

ORD record
ord-ca05e201ea0f4ec2ad478d8dbc3be143
Source dataset
uspto-grants-2015_11
Patent number
US09193733B2

Reaction notes

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