Methanamine, N-methoxy-, hydrochloride (1:1) → (e)-3-(4-Fluorophenyl)-n-methoxy-n,2-dimethylacrylamide

HRID 514657Notes

Reaction equation

HRID 514657 reaction equation
C([Mg]Cl)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14](\[CH3:20])/[C:15](OCC)=[O:16])=[CH:9][CH:8]=1.Cl.[CH3:22][NH:23][O:24][CH3:25]>C1COCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10](/[CH:13]=[C:14](\[CH3:20])/[C:15]([N:23]([O:24][CH3:25])[CH3:22])=[O:16])=[CH:11][CH:12]=1

Participants

5

Reactant 3

HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 12016768(E)-ethyl 3-(4-fluorophenyl)-2-methylacrylateHCID 178418918HCID 178418918, compound

Product 1

HCID 87521933(e)-3-(4-Fluorophenyl)-n-methoxy-n,2-dimethylacrylamideYield 86.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of isopropylmagnesium chloride (2.0 M in THF, 59.1 mL, 118 mmol) was added dropwise via addition funnel to a mixture of Example 1A (5.47 g, 26.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.12 g, 52.5 mmol) in THF (100 mL) at 0° C. Upon complete addition, the reaction was allowed to proceed 2 hr at 0° C. The reaction was quenched by slow addition of saturated aq NH4Cl solution (70 mL). The mixture was stirred 60 min, then partitioned between EtOAc (50 mL) and H2O (100 mL). The separated aqueous phase was extracted with EtOAc, and the combined organic layer was washed with 1 N aq HCl and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash 280; SF65-400 g column; 20% to 60% EtOAc/hexanes; 0-40 min) to give the title compound (5.06 g, 22.7 mmol, 86% yield) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.50-7.40 (m, 2H), 7.29-7.18 (m, 2H), 6.72 (s, 1H), 3.65 (s, 3H), 3.19 (s, 3H), 2.01 (d, J=1.5 Hz, 3H). MS (DCI+) 224 (M+H).

Workup

  1. additionUpon complete addition
  2. customThe reaction was quenched by slow addition of saturated aq NH4Cl solution (70 mL)
  3. custompartitioned between EtOAc (50 mL) and H2O (100 mL)
  4. extractionThe separated aqueous phase was extracted with EtOAc
  5. washthe combined organic layer was washed with 1 N aq HCl and brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by chromatography on silica gel (Analogix® Intelliflash 280; SF65-400 g column; 20% to 60% EtOAc/hexanes; 0-40 min)

Sources & evidence

ORD record
ord-6fbf963d89424837abae7219af2347fa
Source dataset
uspto-grants-2015_08
Patent number
US09108905B2

Reaction notes

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