Sodium Carbonate → 5-(2,4,4-Trimethyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl)thiophene-2-carbonitrile

HRID 2300095Notes

Reaction equation

HRID 2300095 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[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:39]1[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[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>[CH3:11][CH:9]1[O:8][C:7]([CH3:13])([CH3:12])[C:6]2[CH:14]=[C:2]([C:39]3[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=3)[CH:3]=[CH:4][C:5]=2[NH:10]1

Participants

10

Reactant 5

HCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 35950595-Bromothiophene-2-carbonitrileHCID 234355746-Bromo-2,4,4-trimethyl-2,4-dihydro-1H-benzo[D][1,3]oxazine

Product 1

HCID 120431855-(2,4,4-Trimethyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl)thiophene-2-carbonitrileYield 25.1%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
85 °C

Procedure

A mixture of 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine (3.6 g, 14 mmol), bis(pinacolato)diboron (5 g, 19.7 mmol), potassium acetate (4 g, 41 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.4 g, 0.5 mmol) in DMF (80 ml,) was subject to a positive nitrogen flow to remove oxygen and then heated at 85° C. under a blanket of nitrogen for 18 hours. The mixture was allowed to cool to ambient temperature, treated with 5-bromo-2-thiophenecarbonitrile (4 g, 21 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.4 g, 0.5 mmol), and aqueous sodium carbonate solution (2M, 35 mL, 70 mmol), and then heated at 85° C. under nitrogen for 3 hours. The reaction mixture was allowed to cool to ambient temperature, brine (100 mL) and ethyl acetate (150 mL) were added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by a flash silica gel column chromatography(THF:hexane/1:4) to afford the title compound as an off-white solid (1 g, 25%): mp 172-173° C.; 1H-NMR (DMSO-d6) δ 7.88 (d, 1H, J=4.0 Hz), 7.47 (d, 1H, J=4.0 Hz), 7.43 (d, 1H, J=2.0 Hz), 7.32 (dd, 1H, J=8.36, 2.4 Hz), 6.77 (s, 1H), 6.60 (d, 1H, J=8.4 Hz), 4.83 (m, 1H), 1.51 (s, 3H), 1.48 (s, 3H), 1.28 (d, 3H, J=5.6 Hz); MS (ESI) m/z 283 [M−H]−.

Workup

  1. customto remove oxygen
  2. temperatureto cool to ambient temperature
  3. temperatureheated at 85° C. under nitrogen for 3 hours
  4. temperatureto cool to ambient temperature
  5. customThe organic layer was separated
  6. extractionaqueous layer was extracted with ethyl acetate (3×50 mL)
  7. dry with materialThe combined organic layers were dried (MgSO4)
  8. concentrationconcentrated
  9. customThe residue was purified by a flash silica gel column chromatography(THF:hexane/1:4)

Sources & evidence

ORD record
ord-b70aa4df65824c0d9167360b2c14fafd
Source dataset
uspto-grants-2002_12
Patent number
US06498154B1

Reaction notes

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