Dimethylformamide → Tert-butyl 4-fluoro-2-[(methylamino)carbonyl]benzylcarbamate

HRID 2252801Notes

Reaction equation

HRID 2252801 reaction equation
[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4](I)[CH:3]=1.CN.C(N(C(C)C)CC)(C)C.[CH3:29][N:30]([CH:32]=[O:33])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:32]([NH:30][CH3:29])=[O:33])[CH:3]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 6329MethylamineHCID 81531DiisopropylethylamineHCID 21070049Tert-butyl 4-fluoro-2-iodobenzylcarbamate

Product 1

HCID 11984298Tert-butyl 4-fluoro-2-[(methylamino)carbonyl]benzylcarbamate

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
90 °C

Procedure

Through a solution of tert-butyl 4-fluoro-2-iodobenzylcarbamate (1.00 g, 2.85 mmol) in dry DMF (20 mL), in an oven dried glass insert in a high pressure bomb reactor flushed with nitrogen, was bubbled methylamine gas at 0° C. until the solution was saturated and excess methylamine was condensed into the reaction (approximately 30 equivalents of methylamine). Diisopropylethylamine (0.99 mL, 5.70 mmol), palladium acetate (64 mg, 0.29 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (158 mg, -0.29 mmol) were added to the saturated solution. The glass insert was then placed in the pressure vessel and the vessel was purged once with carbon monoxide gas. The vessel was recharged with carbon monoxide gas to pressure of 300 psi, placed into an oil bath, and heated to 90° C. for four hours. The vessel was cooled, the gas was released slowly and the resulting mixture was partitioned between water and ethyl acetate. The layers were separated and the organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to a brown liquid. The residue was purified by flash column chromatography (ISCO column, 110 g silica gel) eluting with a 10-50% acetone/hexane gradient over 35 minutes to afford the desired product as a brown crystalline solid.

Workup

  1. customflushed with nitrogen
  2. customwas bubbled methylamine gas at 0° C. until the solution
  3. customcondensed
  4. customthe vessel was purged once with carbon monoxide gas
  5. customplaced into an oil bath
  6. temperatureThe vessel was cooled
  7. customthe resulting mixture was partitioned between water and ethyl acetate
  8. customThe layers were separated
  9. dry with materialthe organic extracts were dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo to a brown liquid
  12. customThe residue was purified by flash column chromatography (ISCO column, 110 g silica gel)
  13. washeluting with a 10-50% acetone/hexane gradient over 35 minutes

Sources & evidence

ORD record
ord-ca31ad0aae95450887b9747fbbecf8fd
Source dataset
uspto-grants-2008_01
Patent number
US07323460B2

Reaction notes

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