N-bromobutanimide → HCID 68107558, compound

HRID 869100Notes

Reaction equation

HRID 869100 reaction equation
[F:1][C:2]1[C:3]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:14]N1C(=O)CCC1=O>C(OC)(C)(C)C.C(#N)C.CCCCCC>[Br:14][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:2]=1[F:1]

Participants

6

Reactant 2

HCID 67184N-bromobutanimideHCID 68107563HCID 68107563, compound

Product 1

HCID 68107558HCID 68107558, compoundYield 105%

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 8058HexaneSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

To a stirring solution of 3-fluoro-2-tetrahydrofuran-2-yl-aniline (16) (131.9 g, 92%, 669.7 mmol) in methyl tert-butyl ether (1.456 L) and acetonitrile (485 mL) cooled to −20° C. was added N-bromosuccinimide (120.4 g, 99%, 669.7 mmol, Aldrich B81255) in 3 portions maintaining a reaction temperature below about −15° C. After complete addition stirring was continued at −15 to −10° C. for 30 minutes. 1H NMR of a worked-up aliquot showed 96% consumption of starting aniline so added another 4.82 g NBS and stirred at −10° C. for another 30 minutes. Aqueous 1 N Na2S2O3 (670 mL) was added to the reaction mixture. The cold bath was removed, the mixture stirred for 20 minutes, then diluted with EtOAc. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 (2×), water, brine, dried over Na2SO4, decanted, and concentrated under reduced pressure giving a dark amber oil. The residue was diluted with hexane and eluted through a short plug of silica eluting with 25% EtOAc/hexane to 50% EtOAc/hexane. The desired filtrate was concentrated in vacuo giving 17 as a dark amber oil (182.9 g, 90% yield; 86% NMR purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 260.12 (3.20 min). 1H NMR (300 MHz, CDCl3) δ 7.15 (dd, J=8.6, 7.6 Hz, 1H), 6.30 (dd, J=8.7, 1.3 Hz, 1H), 5.19-5.12 (m, 1H), 4.58 (s, 2H), 4.16-4.07 (m, 1H), 3.90-3.81 (m, 1H), 2.23-1.99 (m, 4H) ppm.

Workup

  1. temperaturemaintaining a reaction temperature below about −15° C
  2. additionAfter complete addition
  3. custom96% consumption of starting aniline
  4. additionso added another 4.82 g NBS
  5. stirringstirred at −10° C. for another 30 minutes
  6. additionAqueous 1 N Na2S2O3 (670 mL) was added to the reaction mixture
  7. customThe cold bath was removed
  8. stirringthe mixture stirred for 20 minutes
  9. additiondiluted with EtOAc
  10. customThe layers were separated
  11. washthe organic phase was washed with saturated aqueous NaHCO3 (2×), water, brine
  12. dry with materialdried over Na2SO4
  13. customdecanted
  14. concentrationconcentrated under reduced pressure
  15. customgiving a dark amber oil
  16. washeluted through a short plug of silica eluting with 25% EtOAc/hexane to 50% EtOAc/hexane
  17. concentrationThe desired filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-f68fcc64e1cc4a608ff3aef8ff8f8fba
Source dataset
uspto-grants-2015_03
Patent number
US08969359B2

Reaction notes

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