N-Fluorobenzenesulfonimide → Tert-butyl 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylate

HRID 1405361Notes

Reaction equation

HRID 1405361 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12.[Li]CCCC.C1(S(N([F:52])S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1>C1COCC1>[F:52][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12

Participants

5

Reactant 3

HCID 588007N-FluorobenzenesulfonimideHCID 68153220Tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylateHCID 178418339Butyllithium

Product 1

HCID 68153554Tert-butyl 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylateYield 43%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (15.0 g, 33.2 mmol) in THF (200 mL) was purged with Argon for 5 min. The mixture was cooled to −78° C. before nBuLi (42.5 mL of 1.6 M, 68 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min before a solution of N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (20.9 g, 66.3 mmol) in THF (100 mL) was added dropwise. The mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with sat. aq. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated to dryness. CH2Cl2 was added and the solid was removed via filtration. The filtrate was concentrated to dryness and the residue was purified by column chromatography (10-20% EtOAc-Hex) to provide tert-butyl 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.52 g, 43%) as a light brown oil that solidified upon standing. ESI-MS m/z calc. 391.4, found 392.5 (M+1)+; Retention time: 1.35 minutes (3 minute run).

Workup

  1. additionwas added dropwise
  2. additionwas added dropwise
  3. customThe reaction mixture was quenched with sat. aq. NH4Cl
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with EtOAc (2×)
  6. washwashed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated to dryness
  10. additionCH2Cl2 was added
  11. customthe solid was removed via filtration
  12. concentrationThe filtrate was concentrated to dryness
  13. customthe residue was purified by column chromatography (10-20% EtOAc-Hex)

Sources & evidence

ORD record
ord-552241a20c3545648ccfe823ec8cbdb4
Source dataset
uspto-grants-2014_12
Patent number
US08916565B2

Reaction notes

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