Sodium Carbonate → 3-[(2R,4S)-2,4-Dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl]-5-fluorobenzonitrile

HRID 2300099Notes

Reaction equation

HRID 2300099 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:18])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:19]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C@H:9]1[O:8][C@@:7]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:19]=[C:2]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=3)[C:20]#[N:21])[CH:3]=[CH:4][C:5]=2[NH:10]1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 234355826-bromo-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazineHCID 23435605(3-Cyano-5-fluorophenyl)boronic acid

Product 1

HCID 120431863-[(2R,4S)-2,4-Dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl]-5-fluorobenzonitrileYield 13.2%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 6-bromo-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazine (0.6 g, 1.9 mmol), 3-cyano-5-fluorobenzene boronic acid (0.45 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium (0) (0.2 g, 0.17 mmol), sodium carbonate (0.6 g, 5.7 mmol) in a mixture of DME and water (20/5 mL) was subject to a positive nitrogen flow to remove oxygen and then heated to 85° C. under a blanket of nitrogen for 2 hours. The mixture was allowed to cool to ambient temperature. Brine (30 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4), and evaporated. The residue was purified by a silica gel column chromatography(hexane:ethyl acetate/4:1) to afford the title compound as off-white solid (0.09 g, 13%): mp128-129° C.; 1H-NMR (DMSO-d6) δ 8.08 (s, 1H), 7.91 (dt, 1H, J=10.7, 1.9 Hz), 7.71 (d, 1H, J=2.0 Hz), 7.65 (m, 1H), 7.57 (dd, 1H, J=8.8, 2.4 Hz), 7.32-7.36 (m, 2H), 7.24-7.29 (m, 3H), 6.71 (d, 1H, J=1.6 Hz), 6.69 (d, 1H, J=8.3 Hz), 4.33 (m, 1H), 1.84 (s, 3H), 1.24 (d, 3H, J=5.5 Hz); MS (ESI) m/z 357 [M−H]−.

Workup

  1. customto remove oxygen
  2. temperatureto cool to ambient temperature
  3. additionBrine (30 mL) and ethyl acetate (100 mL) were added
  4. customThe organic layer was separated
  5. extractionaqueous layer was extracted with ethyl acetate (3×30 mL)
  6. dry with materialThe combined organic layers were dried (MgSO4)
  7. customevaporated
  8. customThe residue was purified by a silica gel column chromatography(hexane:ethyl acetate/4:1)

Sources & evidence

ORD record
ord-2ff2ff0dbaac46b9b52e5ec20301120b
Source dataset
uspto-grants-2002_12
Patent number
US06498154B1

Reaction notes

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