(Diethylamino)sulfur trifluoride → (2R,4S)-tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate

HRID 513006Notes

Reaction equation

HRID 513006 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][C@@H:11](O)[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1.CCN(S(F)(F)[F:27])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C@@H:11]1[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1.[F:27][C@@H:11]1[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1

Participants

6

Reactant 3

HCID 123472(Diethylamino)sulfur trifluorideHCID 516892Sodium BicarbonateHCID 66684241(4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate

Product 2

HCID 66684235(2R,4S)-tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylateHCID 66685044(2S,4S)-tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of (4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-4) (2.7 g, 9.6 mmol) in DCM (25 mL) in a plastic bottle at −78° C. was added DAST (2.5 mL, 19.2 mmol). The mixture was stirred at −78° C. for 2 hours and then was warmed slowly to room temperature overnight. The mixture was added drop wise to aqueous NaHCO3 at 0° C. and was extracted with DCM. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The two diasteromers were separated by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield (2R,4S)-tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-5A) (first eluting compound) and (2S,4S)-tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-5B). 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J=6.0, 6.0 Hz, 1 H), 6.92 (bd, J=8.0 Hz, 1 H), 6.88-6.82 (m, 2 H), 5.20 (bd, J=52.0 Hz, 1 H), 4.80 (bs, 1 H), 4.02 (dd, J=13.6, 22.8 Hz, 1 H), 3.65 (dd, J=12.8, 38.4 Hz, 1 H), 2.67-2.56 (m, 1 H), 1.89 (dt, J=11.2, 42 Hz, 1 H), 1.09 (s, 6 H). MS m/z 284.1 (M+1)+.

Workup

  1. temperaturewas warmed slowly to room temperature overnight
  2. extractionwas extracted with DCM
  3. washwashed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe two diasteromers were separated by column chromatography on silica gel with EtOAc/hexanes gradient as eluant

Sources & evidence

ORD record
ord-09981be5a5664b31b744e2001bd9a836
Source dataset
uspto-grants-2015_08
Patent number
US09102671B2

Reaction notes

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