Trifluoroacetic acid → (R)-4,4-difluoro-2-(3-fluorophenyl)pyrrolidine

HRID 513009Notes

Reaction equation

HRID 513009 reaction equation
C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:14][C:11]1([F:13])[CH2:12][NH:8][C@@H:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:10]1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 66684270(R)-tert-butyl 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate

Product 1

HCID 66684260(R)-4,4-difluoro-2-(3-fluorophenyl)pyrrolidine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (R)-tert-butyl-4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-8) (0.9 g, 3.0 mmol) in DCM (20 mL) was added TFA (2 mL, 27 mmol) and stirred at room temperature for 2 hours. The reaction was cooled to 0° C. and aqueous NaHCO3 was added while rapidly stirring. The organic phase was separated and washed with aqueous NaHCO3, dried over anhydrous sodium sulfate, filtered and reduced to dryness to yield (R)-4,4-difluoro-2-(3-fluorophenyl)pyrrolidine (I-9) as a light yellow oil that crystallizes on standing. 1H NMR (400 MHz, CD3OD) δ 7.40 (q, J=8.0 Hz, 1 H), 7.23 (d, J=8.8 Hz, 1 H), 7.20 (d, J=10.0 Hz, 1 H), 7.05 (dt, J=8.8, 2.4 Hz, 1 H), 4.41 (dd, J=10.4, 7.2 Hz, 1 H), 3.48 (q, J=12.0 Hz, 1 H), 3.30 (q, J=15.2 Hz, 1 H), 2.74-2.63 (m, 1 H), 2.29-2.14 (m, 1 H). MS m/z 202.1 (M+1)+.

Workup

  1. temperatureThe reaction was cooled to 0° C.
  2. stirringwhile rapidly stirring
  3. customThe organic phase was separated
  4. washwashed with aqueous NaHCO3
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered

Sources & evidence

ORD record
ord-aa22eb6c4b9142d69dbb8f921ba9d596
Source dataset
uspto-grants-2015_08
Patent number
US09102671B2

Reaction notes

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