Sodium Carbonate → 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile

HRID 413181Notes

Reaction equation

HRID 413181 reaction equation
Br[C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([F:49])[CH:48]=1)[C:44]#[N:45].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[CH3:12][C:7]1([CH3:13])[C:6]2[CH:14]=[C:2]([C:41]3[CH:42]=[C:43]([CH:46]=[C:47]([F:49])[CH:48]=3)[C:44]#[N:45])[CH:3]=[C:4]([O:15][CH3:16])[C:5]=2[NH:10][C:9](=[O:11])[O:8]1

Participants

11

Reactant 5

HCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 27833303-Bromo-5-fluorobenzonitrileHCID 235096426-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Product 1

HCID 235096143-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrileYield 33%

Reagents, catalysts & solvents 5

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.6 g, 5.6 mmol), bis(pinacolato)diboron (1.6 g, 6.3 mmol), potassium acetate (1.5 g, 15.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol) in DMF (30 mL) was subject to a positive flow of nitrogen to remove oxygen and then heated at 85° C. under a blanket of nitrogen for 18 hours. The reaction mixture was allowed to cool to ambient temperature, treated with 3-bromo-5-fluoro-benzonitrile (1.2 g, 6 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol), and sodium carbonate (2 g, 19 mmol) in water (10 mL). The resulted solution was heated at 85° C. for 3 hours under a blanket of nitrogen, cooled to rt, and treated with brine (50 mL). Ethyl acetate (100 mL) was added, organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a flash silica gel column chromatography (THF:hexane/2:3) to yield 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile as a white solid (0.6 g, 33%): mp 252-253° C.; 1H-NMR (DMSO-d6) δ9.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, J=10.6 Hz), 7.82 (m,1H), 7.39 (s 1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z 325 [M−H]−.

Workup

  1. customto remove oxygen
  2. temperatureto cool to ambient temperature
  3. temperatureThe resulted solution was heated at 85° C. for 3 hours under a blanket of nitrogen
  4. temperaturecooled to rt
  5. customorganic layer was separated
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe residue was purified by a flash silica gel column chromatography (THF:hexane/2:3)

Sources & evidence

ORD record
ord-e2b73d60934547a196355de6370abd97
Source dataset
uspto-grants-2003_05
Patent number
US06566358B2

Reaction notes

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