Ethyl Acetate → 3-(4,4-Dimethyl-2-trifluoromethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile

HRID 277868Notes

Reaction equation

HRID 277868 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=2[CH:17]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1)#[N:19].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][C:7]1([CH3:16])[C:6]2[CH:17]=[C:2]([C:22]3[CH:21]=[C:20]([CH:25]=[C:24]([F:26])[CH:23]=3)[C:18]#[N:19])[CH:3]=[CH:4][C:5]=2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8]1

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 234355726-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazineHCID 23435605(3-Cyano-5-fluorophenyl)boronic acid

Product 1

HCID 234355873-(4,4-Dimethyl-2-trifluoromethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrileYield 73%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine (0.5 g, 1.61 mmol), 3-cyano-5-fluorobenzeneboronic acid (0.39 g, 1.8 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.2 g, 0.161 mmol), and sodium carbonate (0.5 g, 4.83 mmol) in DME (50 mL) and water (25 mL) was subject to a blanket of nitrogen flow for 15 minutes at 50° C. and then was heated at 85° C. under nitrogen for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate (200 mL) was added. The organic layer was washed twice with aqueous ammonium chloride (20 mL) and once with brine (20 mL), dried over sodium sulfate and concentrated to a yellow solid. Purification via flash column chromatography (silica gel, 5% ethyl acetate/hexane) gave 3-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]-5-fluorobenzonitrile (0.396 g, 73%) as a white solid: mp 102-103° C.; 1H-NMR (DMSO-d6) δ 8.07 (s, 1H), 7.91 (d, 1H, J=10.7 Hz), 7.7 (d, 1H, J=10.7 Hz) 7.62 (d, 1H, J=1.98 Hz), 7.53 (dd, 1H, J=8.33, 1.98 Hz), 7.05 (s, 1H), 6.87 (d, 1H, J=8.33 Hz), 5.39-5.37 (m, 1H), 1.61 (s, 3H), 1.59 (s, 3H); MS (ES) m/z 349 ([M−H]−).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washThe organic layer was washed twice with aqueous ammonium chloride (20 mL) and once with brine (20 mL)
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated to a yellow solid
  5. customPurification via flash column chromatography (silica gel, 5% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-c5cbbeb8b8964c749f00297c606153ee
Source dataset
uspto-grants-2002_03
Patent number
US06358948B1

Reaction notes

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