18-Crown-6 → 4-[(6-Chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrile

HRID 1875209Notes

Reaction equation

HRID 1875209 reaction equation
[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[F:44]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=2[F:44])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 2855718-Crown-6HCID 27736846-Chloro-2-fluoro-3-methylphenolHCID 151654434-Bromo-3-fluorobenzonitrileHCID 23665647Potassium tert-butoxide

Product 1

HCID 687209894-[(6-Chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrileYield 81%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 6-chloro-2-fluoro-3-methylphenol (3.25 g, 20.24 mmol) and 18-crown-6 (0.535 g, 2.024 mmol) in DMSO (40 ml) was added potassium tert-butoxide (20 wt % in THF) (12.49 g, 22.26 mmol) and the reaction mixture was stirred at rt for 30 minutes. Next, 4-bromo-3-fluorobenzonitrile (4.05 g, 20.24 mmol) was added and the reaction mixture stirred at 135° C. for 3 days. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrile (4.56 g, 16.30 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (dd, 1H), 7.59 (d, 1H), 7.35-7.43 (m, 1H), 7.30 (t, 1H), 6.89 (t, 1H), 2.24 (d, 3H).

Workup

  1. stirringthe reaction mixture stirred at 135° C. for 3 days
  2. washwashed with water
  3. customThe solvent was removed
  4. customthe crude material was purified via silica gel chromatography

Sources & evidence

ORD record
ord-99238988f1744ea5a6b02c82d1da045c
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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