Isopropanol → 1-(3-Fluorophenyl)cyclobutane-1-carbonitrile

HRID 260170

Reaction equation

HRID 260170 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.Br[CH2:14][CH2:15][CH2:16]Br.C(O)(C)C>CS(C)=O.CCOCC.O>[F:3][C:4]1[CH:5]=[C:6]([C:10]2([C:11]#[N:12])[CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1

Participants

8

Reactant 4

HCID 3776IsopropanolHCID 80011,3-DibromopropaneHCID 24758Sodium hydrideHCID 68145Benzeneacetonitrile, 3-fluoro-

Product 1

HCID 224027611-(3-Fluorophenyl)cyclobutane-1-carbonitrileYield 57.2%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
0 °C

Procedure

CHART B, Preparation of the amine used in Chart B, Step B-2. A stirred suspension of freshly washed and dried sodium hydride (50% by wt, 9.59 g, 200 mmol) in dry dimethyl sulfoxide (75 mL) under N2 is cooled to 0° C. A mixture of 3-fluorophenylacetonitrile (8.6 mL, 74.0 mmol) and 1,3-dibromopropane (8.3 mL, 81.4 mmol) in ether (40 mL) is then added dropwise over 35 minutes, via cannula. The resulting orange-red mixture is allowed to stir at 20°-25° C. overnight. The thick reaction mixture is cooled to 0° C. and treated with isopropanol (4 mL). After stirring for 15 minutes, water (64 mL) is added in 10 mL increments and the phases are separated. The aqueous layer is extracted with ether (4×100 mL). The combined organics are washed with water (3×100mL), brine (1×100 mL), dried (MgSO4), filtered and concentrated. The product is distilled at 95° C. (1.0 torr) to afford 7.41 g of 1-(3-fluorophenyl)cyclobutanecarbonitrile. 1H NMR (CDCl3) δ7.39 (m, 1 H), 7.19 (m, 1 H), 7.13 (m, 1 H), 7.05 (m, 1 H), 2.81 (m, 2 H), 2.60 (m, 4 H), 2.50 (m, 1 H), 2.12 (m, 1 H); 13C NMR (CDCl3) δ164.6, 161.3, 142.2, 130.6, 130.5, 123.8, 121.37, 121.32, 115.0, 114.7, 113.0, 112.7, 77.2, 40.9, 39.9, 34.6, 17.0.

Workup

  1. additionA stirred suspension
  2. washof freshly washed
  3. additionis then added dropwise over 35 minutes, via cannula
  4. stirringAfter stirring for 15 minutes
  5. customthe phases are separated
  6. extractionThe aqueous layer is extracted with ether (4×100 mL)
  7. washThe combined organics are washed with water (3×100mL), brine (1×100 mL)
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. distillationThe product is distilled at 95° C. (1.0 torr)

Sources & evidence

ORD record
ord-bdae9d71641f4c448acf8139f0fa25a8
Source dataset
uspto-grants-1996_06
Patent number
US05525742

Linked notes

Loading…