Acetyl chloride → 4-(1-Acetyl-4,4-dimethyl-2-trifluoromethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile

HRID 2300116Notes

Reaction equation

HRID 2300116 reaction equation
[CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([C:17]#[N:18])[S:15][CH:16]=3)[CH:10]=[CH:11][C:6]=2[NH:5][CH:4]([C:19]([F:22])([F:21])[F:20])[O:3]1.[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>CN(C=O)C.[Cl-].[Na+].O>[C:26]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([C:17]#[N:18])[S:15][CH:16]=3)=[CH:8][C:7]=2[C:2]([CH3:23])([CH3:1])[O:3][CH:4]1[C:19]([F:22])([F:20])[F:21])(=[O:28])[CH3:27]

Participants

6

Reactant 3

HCID 6367Acetyl chlorideHCID 24758Sodium hydrideHCID 234355804-[2-(Trifluoromethyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-6-yl]-2-thiophenecarbonitrile

Product 1

HCID 234355944-(1-Acetyl-4,4-dimethyl-2-trifluoromethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrileYield 36%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

4-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]thiophene-2-carbonitrile (0.25 g, 0.74 mmol) was dissolved in DMF (10 mL), NaH (0.09 g, 2.22 mmol) was added and the mixture was stirred for 30 minutes prior to the addition of acetyl chloride (0.079 mL, 1.11 mmol). Upon disappearance of the starting material the reaction mixture was poured into brine (100 mL) and the product extracted with ether (150 mL), dried over sodium sulfate and concentrated. The residue was purified by a flash column chromatography (silica gel, 25% ethyl acetate/hexane) to yield 4-[1-acetyl-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]thiophene-2-carbonitrile (0.1 g, 36%) as an amorphous solid: 1H-NMR (DMSO-d6) δ 8.58 (s, 1H), 8.5 (s, 1H), 7.83-7.80 (m, 2H), 7.64 (d, 1H, J=8.74 Hz), 6.42 (q, 1H, J=10 Hz), 2.24 (s, 3H), 1.73 (s, 3H), 1.42 (s, 3H). EXAMPLE 35 (6(5-Cyanothien-3-yl)-4,4-dimethyl-2(tnfluoromethyl)-2H-3,1-benzoxazin-1(4H)-yl)methyl Pivalate 4-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]thiophene-2-carbonitrile (0.30 g, 0.89 mmol) was dissolved in DMF (10 mL), NaH (0.065 g, 2.7 mmol) was added and the was mixture stirred for 30 minutes prior to the addition of tert-butyl chloroacetate (0.19 mL, 1.3 mmol). Upon disappearance of the starting material the reaction mixture was poured into brine (100 mL) and the product extracted with ether (150 mL), dried over sodium sulfate and concentrated. Flash column chromatography (silica gel, 8% ethyl acetate/hexane) gave (6(5-cyanothien-3-yl)-4,4-dimethyl-2-(trifluoromethyl)-2H-3,1-benzoxazin-1 (4H)-yl)methyl pivalate (0.127 g, 32%) as an amorphous solid: 1H-NMR (CDCl3) δ 7.82 (s, 1H), 7.58 (s, 1H), 7.41 (dd, 1H, J=8.33, 1.98 Hz), 7.25 (d, 1H, J=1.98 Hz) 7.10 (d, 1H, J=8.33 Hz), 6.79 (d, 1H, J=8.33 Hz), 5.66 (d, 1H, J=11.9 Hz), 5.38 (d, 1H, J=11.9 Hz), 1.72 (s, 3H), 1.55 (s, 3H), 1.18 (s, 9H).

Workup

  1. extractionthe product extracted with ether (150 mL)
  2. dry with materialdried over sodium sulfate
  3. concentrationconcentrated
  4. customThe residue was purified by a flash column chromatography (silica gel, 25% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-27a6ae3edbac4a5f8fcd3fdd38d258b5
Source dataset
uspto-grants-2002_12
Patent number
US06498154B1

Reaction notes

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