Dichloromethane → (R)-2-(Bis(3,5-bis(trifluoromethyl)phenyl)((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine

HRID 1959889Notes

Reaction equation

HRID 1959889 reaction equation
[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.C(Cl)Cl.FC(F)(F)S(O[Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])(=O)=O>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([O:14][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[CH:4]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:8]=1

Participants

5

Reactant 4

HCID 6344DichloromethaneHCID 8471TriethylamineHCID 123564tert-Butyldimethylsilyl trifluoromethanesulphonateHCID 71310462(2R)-alpha,alpha-Bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol

Product 1

HCID 60203151(R)-2-(Bis(3,5-bis(trifluoromethyl)phenyl)((tert-butyldimethylsilyl)oxy)methyl)pyrrolidineYield 91.2%

Procedure

To a stirred solution of (2R)-bis(3,5-bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol ((R)-33, 1.051 g, 2.0 mmol) and triethylamine (TEA, 1.68 mL, 12.0 mmol, 6.0 equiv) in anhydrous methylene chloride (5.0 mL, 78 mmol) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf, 1.41 mL, 6.0 mmol, 3.0 equiv). The resulting reaction mixture was stirred at room temperature for 20 h before being heated at 100° C. for 10-20 h. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2) with 0-10% EtOAc/hexane gradient elution to give (2R)-2-(bis[3,5-bis(trifluoromethyl)phenyl][tert-butyl(dimethyl)silyl]oxymethyl)pyrrolidine ((R)-36, 1.167 g, 1.279 g theoretical, 91.2% yield) as a very viscous colorless syrup. For (R)-36: 1H NMR (CDCl3, 400 MHz) δ ppm 8.09 (s, 2H), 7.87 (s, 2H), 7.75 (s, 2H), 4.33 (m, 1H), 2.98 (m, 1H), 2.54 (m, 1H), 1.86 (m, 1H), 1.70 (m, 1H), 1.56 (m, 2H), 0.95 (s, 9H), −0.21 (s, 3H), −0.45 (s, 3H); C27H29F12NOSi (MW, 639.59), LCMS (EI) m/e 640.4 (M++H).

Workup

  1. customThe resulting reaction mixture
  2. temperaturebefore being heated at 100° C. for 10-20 h
  3. customthe reaction mixture was quenched with water (30 mL)
  4. extractionextracted with EtOAc (2×50 mL)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over magnesium sulfate (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by Combiflash (SiO2) with 0-10% EtOAc/hexane gradient elution

Sources & evidence

ORD record
ord-1ca6e9319f72411286f452051e86d5e4
Source dataset
uspto-grants-2013_04
Patent number
US08410265B2

Reaction notes

Loading…