4-Piperidinol, 1-methyl- → 4-(1-Methylpiperidin-4-yloxy)-3-trifluoromethylbenzonitrile

HRID 1919826Notes

Reaction equation

HRID 1919826 reaction equation
[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[C:24]([F:27])([F:26])[F:25]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:1][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[C:24]([F:25])([F:27])[F:26])[CH2:3][CH2:4]1

Participants

5

Reactant 3

HCID 660484-Piperidinol, 1-methyl-HCID 1442554-Fluoro-3-(trifluoromethyl)benzonitrileHCID 23665647Potassium tert-butoxide

Product 1

HCID 231459404-(1-Methylpiperidin-4-yloxy)-3-trifluoromethylbenzonitrileYield 55.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 4-hydroxy-N-methylpiperidine (133 mg, 1.15 mmol) and potassium tert-butoxide (150 mg, 1.27 mmol) in tetrahydrofuran (2.5 mL) was stirred under nitrogen for 10 min. 4-Fluoro-3-(trifluoromethyl)benzonitrile (218 mg, 1.15 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo, and the residue was partitioned between a 1 M NaOH solution and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3/MeOH/conc. NH3, 95:5:0.5) affording 0.18 g (54% yield) of the pure product as a colourless solid. MS (APCI) m/z 285 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.67-1.74 (m, 2 H), 1.89-1.95 (m, 2 H), 2.16 (s, 3 H), 2.26-2.31 (m, 2 H), 2.44-2.48 (m, 2 H), 4.78-4.82 (m, 1 H), 7.51 (d, J=8.8 Hz, 1 H), 8.08 (dd, J=8.8, 2.0 Hz, 1 H), 8.14 (d, J=2.0 Hz, 1 H).

Workup

  1. stirringthe reaction mixture was stirred at ambient temperature for 1 h
  2. customThe solvent was removed in vacuo
  3. customthe residue was partitioned between a 1 M NaOH solution and ethyl acetate
  4. dry with materialThe organic layer was dried (Na2SO4)
  5. customevaporated
  6. customThe residue was purified by column chromatography on silica gel (eluent: CHCl3/MeOH/conc. NH3, 95:5:0.5)

Sources & evidence

ORD record
ord-79e86683d3584337bf312eacf8691a5b
Source dataset
uspto-grants-2012_05
Patent number
US08168668B2

Reaction notes

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