Cyclohexanol → HCID 66745877, compound

HRID 2410164Notes

Reaction equation

HRID 2410164 reaction equation
[CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]=1[C:13]#[N:14]

Participants

5

Reactant 3

HCID 7966CyclohexanolHCID 24758Sodium hydrideHCID 5226592-Amino-6-fluorobenzonitrile

Product 1

HCID 66745877HCID 66745877, compoundYield 56%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of cyclohexanol (19.1 g, 0.191 mol) in anhydrous THF (500 mL) was added NaH (7.6 g, 40% in mineral oil, 0.191 mol) in small portions at 0° C. under nitrogen. The mixture was stirred at room temperature for 1 h and a solution of 2-amino-6-fluorobenzonitrile (20.0 g, 0.15 mol) in anhydrous THF (150 mL) was added drop-wise at room temperature. The reaction mixture was heated to reflux overnight then cooled to room temperature and most of the THF removed under reduced pressure. Ice water (100 mL) was added to the concentrated reaction mixture followed by EtOAc (500 mL). The organic layer was separated and successively washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 25-30% EtOAc in hexanes to give 2-amino-6-(cyclohexyloxy)benzonitrile as a light yellow oil (17.9 g, 56%). NMR (400 MHz, CDCl3) δ 1.32-1.43 (m, 3H), 1.51-1.55 (m, 1H), 1.62-1.69 (m, 2H), 1.79-1.95 (m, 4H), 4.31-4.36 (m, 3H), 6.23-6.27 (m, 2H), 7.18 (d, J=8.0 Hz, 1H). MS 329 (MH+).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux overnight
  3. customremoved under reduced pressure
  4. additionIce water (100 mL) was added to the concentrated reaction mixture
  5. customThe organic layer was separated
  6. washsuccessively washed with water and brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. customevaporated under reduced pressure
  10. customThe residue was purified by chromatography on silica gel eluting with 25-30% EtOAc in hexanes

Sources & evidence

ORD record
ord-0f08f280888942bb8e725b0e7cfe9987
Source dataset
uspto-grants-2014_08
Patent number
US08815956B2

Reaction notes

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