Dimethylformamide → 3-(4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile

HRID 50708Notes

Reaction equation

HRID 50708 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:25]=[CH:24][C:12]3[NH:13][C:14](=[O:23])[O:15][C:16]([CH:20]4[CH2:22][CH2:21]4)([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH4+].[Cl-].[CH3:28][N:29](C=O)C>[C-]#N.[C-]#N.[Zn+2].[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>[CH:20]1([C:16]2([CH:17]3[CH2:18][CH2:19]3)[O:15][C:14](=[O:23])[NH:13][C:12]3[CH:24]=[CH:25][C:9]([C:4]4[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=4)[C:28]#[N:29])=[CH:10][C:11]2=3)[CH2:22][CH2:21]1

Participants

6

Reactant 3

HCID 6228DimethylformamideHCID 25517Ammonium ChlorideHCID 101579196-(3-Bromo-5-fluoro-phenyl)4,4-dicyclopropyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one

Product 1

HCID 102914083-(4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrileYield 4.6%

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 11979704Tetrakis(triphenylphosphine)palladiumCatalyst

Conditions

Temperature
85 °C

Procedure

A mixture of 6-(3-bromo-5-fluoro-phenyl)-4,4-dicyclopropyl-1,4-dihydro-benzo-[d][1,3]oxazin-2-one (0.4 g, 1.0 mmol), Zn(CN)2 (0.71 g, 0.61 mmol), and tetrakis(triphenylphosphine)-palladium (0) (0.07 g, 0.06 mmol) in DMF (20 mL) was subject to a blanket of nitrogen for 15 minutes at 50° C. and then was heated at 85° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into NH4Cl (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were washed with brine, dried over MgSO4, and concentrated. The clear oil obtained was triturated with ether (30 ml) to give a white solid. Recrystallization of the solid from ethyl acetate gave 3-(4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile (0.016 g, 4.6%): mp 250-252° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 8.12 (s, 1H), 7.97 (d, 1H, J=10.54 Hz), 7.81-7.79 (m, 2H), 7.73 (dd, 1H, J=8.3, 1.59 Hz), 6.94 (d, 1H, J=8.34 Hz), 1.59 (m, 2H), 0.58-0.42 (m, 6H), 0.30-0.28 (m, 2H); MS (ESI) m/z 347 ([M−H]−, 100%); Anal. Calc. For C21H17FN2O2: C, 72.4; H, 4.92; N, 8.04. Found: C, 72.4; H, 4.74; N, 7.61.

Workup

  1. temperatureAfter cooling to room temperature
  2. extractionextracted with ethyl acetate (3×50 mL)
  3. washThe organic layers were washed with brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated
  6. customThe clear oil obtained
  7. customwas triturated with ether (30 ml)
  8. customto give a white solid
  9. customRecrystallization of the solid from ethyl acetate

Sources & evidence

ORD record
ord-ef2b7827bafc435cb83f56570e0654fe
Source dataset
uspto-grants-2004_03
Patent number
US06713478B2

Reaction notes

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