1-Bromo-2,4-difluorobenzene → (S)-N-((R)-2-(tert-butyldimethylsilyloxy)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

HRID 539085Notes

Reaction equation

HRID 539085 reaction equation
[Mg].C([Mg]Cl)(C)C.Br[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15].[Si:16]([O:23][CH2:24]/[CH:25]=[N:26]/[S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1.C1(C)C=CC=CC=1>[Si:16]([O:23][CH2:24][C@H:25]([NH:26][S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]

Participants

8

Reactant 4

HCID 676741-Bromo-2,4-difluorobenzene2×HCID 5462224MagnesiumHCID 16007023(NE,S)-N-[2-[tert-butyl(dimethyl)silyl]oxyethylidene]-2-methylpropane-2-sulfinamideHCID 178418918HCID 178418918, compound

Product 1

HCID 67033078(S)-N-((R)-2-(tert-butyldimethylsilyloxy)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamideYield 54%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranCatalystHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
30 °C

Procedure

To a first flask was added magnesium turnings (197 mg, 8.11 mmol) and THF (7 mL). A 2.0 M solution of isopropyl magnesium chloride in THF (16 μL, 0.032 mmol) was added followed by 1-bromo-2,4-difluorobenzene (0.10 mL). The temperature of the reaction mixture raised to 30° C. Additional 1-bromo-2,4-difluorobenzene (0.91 mL) was added dropwise at such a rate that the internal temperature did not exceed 32° C. After addition, the reaction mixture was stirred at 26-28° C. for 30 minutes. To a second flask was added (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 5.41 mmol) and toluene (32 mL) under N2. The reaction mixture was cooled to −78° C. The Grignard reagent prepared in the first flask was slowly transferred to the reaction mixture in the second flask using a syringe. The reaction was allowed to slowly warm up to 0° C. The reaction was quenched by the addition of saturated aqueous NH4Cl solution. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane/EtOAc, 6:1) to give (S)—N—((R)-2-(tert-butyldimethylsilyloxy)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.14 g, 54%) as a white solid.

Workup

  1. customdid not exceed 32° C
  2. additionAfter addition
  3. temperatureThe reaction mixture was cooled to −78° C
  4. temperatureto slowly warm up to 0° C
  5. customThe reaction was quenched by the addition of saturated aqueous NH4Cl solution
  6. customThe organic layer was separated
  7. extractionThe aqueous layer was extracted with EtOAc
  8. washThe combined organic layer was washed with brine
  9. customdried
  10. concentrationconcentrated
  11. customThe residue was purified by column chromatography (hexane/EtOAc, 6:1)

Sources & evidence

ORD record
ord-c4d6226acd1a41f09aeff699ca5d8fe2
Source dataset
uspto-grants-2014_10
Patent number
US08865726B2

Reaction notes

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