N-Methoxy-N-methylacetamide → 2-(4-Acetyl-2-chlorophenyl)-2-methylpropanenitrile

HRID 603137Notes

Reaction equation

HRID 603137 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1)(=[O:24])[CH3:23]

Participants

6

Reactant 3

HCID 537505N-Methoxy-N-methylacetamideHCID 587626012-(4-Bromo-2-chlorophenyl)-2-methylpropanenitrileHCID 178418339Butyllithium

Product 1

HCID 582985122-(4-Acetyl-2-chlorophenyl)-2-methylpropanenitrileYield 64.4%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

To a stirred solution of 2-(4-bromo-2-chlorophenyl)-2-methylpropanenitrile (2.85 g, 11.0 mmol) in anhydrous THF (60 mL) at −78° C. is added n-butyllithium (2 M in c-hexane) (6.1 mL, 12.1 mmol). The reaction mixture is stirred at this temperature 10 min., then N-methoxy-N-methyl-acetamide (2.34 mL, 22.0 mmol) is added neat and the solution is stirred 10 min. at −78° C. and then warmed up to room temperature for another hour. Acidic brine (60 mL) is then slowly added and the solution is extracted with EtOAc (3×60 mL). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (eluent: Hex/EtOAc 1:0 to 7:3) to provide the expected product 2-(4-acetyl-2-chlorophenyl)-2-methylpropanenitrile (1.57 g, 64%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.96 (1H, d, J=1.9 Hz), 7.81 (1H, dd, J=8.3, 1.9 Hz), 7.55 (1H, d, J=8.3 Hz), 2.56 (3H, s), 1.85 (6H, s).

Workup

  1. stirringthe solution is stirred 10 min. at −78° C.
  2. extractionthe solution is extracted with EtOAc (3×60 mL)
  3. dry with materialThe organic layer is dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product is purified by flash chromatography (eluent: Hex/EtOAc 1:0 to 7:3)

Sources & evidence

ORD record
ord-90c4e0d3e607426fb8ccf7a40edce11a
Source dataset
uspto-grants-2011_03
Patent number
US07906654B2

Reaction notes

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