Sodium Iodide → Diethyl 2-acetamido-2-((3,3-difluorocyclobutyl)methyl)malonate

HRID 2355447Notes

Reaction equation

HRID 2355447 reaction equation
BrC1C=CC(S(O[CH2:12][CH:13]2[CH2:16][C:15]([F:18])([F:17])[CH2:14]2)(=O)=O)=CC=1.[Na+].[I-].[H-].[Na+].[CH2:23]([O:25][C:26](=[O:37])[CH:27]([NH:33][C:34](=[O:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24].S(C1C=CC(Br)=CC=1)([O-])(=O)=O.[I-]>CN(C=O)C>[C:34]([NH:33][C:27]([CH2:12][CH:13]1[CH2:14][C:15]([F:17])([F:18])[CH2:16]1)([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([O:25][CH2:23][CH3:24])=[O:37])(=[O:36])[CH3:35]

Participants

8

Reactant 6

HCID 5238Sodium Iodide2×HCID 14041Acetamidomalonic acid diethyl esterHCID 24758Sodium hydrideHCID 30165Iodide IonHCID 15516194-BromobenzenesulfonateHCID 59382908HCID 59382908, compound2×

Product 1

HCID 67189917Diethyl 2-acetamido-2-((3,3-difluorocyclobutyl)methyl)malonate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
0 °C

Procedure

(3,3-Difluorocyclobutyl)methyl 4-bromobenzenesulfonate (500 mg, 1.47 mmol) and NaI (220 mg, 1.47 mmol, 1.0 equiv) were stirred in dry DMF (4 mL). In a separate 3-neck, 100 mL flask NaH (60 wt % in oil, 352 mg, 8.82 mmol, 6 equiv) was slurried in dry DMF (20 mL). The flask was cooled to 0° C. and diethyl-2-acetamidomalonate was added via syringe. After gas evolution ceased, the solution of the (3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate and NaI In DMF was added. The resulting solution was heated to 45° C. for 17 h. After this time no remaining brosylate or iodide was observed by TLC and LC-MS. The mixture was quenched by dropwise addition of water (10 mL) and the DMF was removed in vacuo. The residue was partitioned between ether and water and the layers separated. The aqueous layer was extracted with additional ether and the combined organic layers were washed with brine. The residue was evaporated and the desired product was purified by flash chromatography on silica, eluting with 0 to 50% EtOAc in hexanes. The fractions were stained with ceric ammonium molybdate; the desired product is contained in the second spot. This afforded diethyl 2-acetamido-2-((3,3-difluorocyclobutyl)methyl)malonate (474 mg, 99%).

Workup

  1. temperatureThe resulting solution was heated to 45° C. for 17 h
  2. customThe mixture was quenched by dropwise addition of water (10 mL)
  3. customthe DMF was removed in vacuo
  4. customThe residue was partitioned between ether and water
  5. customthe layers separated
  6. extractionThe aqueous layer was extracted with additional ether
  7. washthe combined organic layers were washed with brine
  8. customThe residue was evaporated
  9. customthe desired product was purified by flash chromatography on silica
  10. washeluting with 0 to 50% EtOAc in hexanes

Sources & evidence

ORD record
ord-2b8bb72bbe894dc29562c4c3c0a251c9
Source dataset
uspto-grants-2010_07
Patent number
US07754737B2

Reaction notes

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