Lawesson's reagent → tert-butyl (4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate

HRID 530285Notes

Reaction equation

HRID 530285 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C@:16]1([CH3:27])[C:21]([F:23])([F:22])[CH2:20][C:19]([F:25])([CH3:24])[C:18](=O)[NH:17]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C@:16]1([CH3:27])[C:21]([F:23])([F:22])[CH2:20][C@@:19]([F:25])([CH3:24])[C:18](=[S:37])[NH:17]1

Participants

4

Reactant 2

HCID 87949Lawesson's reagentHCID 118337839tert-butyl (4-fluoro-3-((2R)-3,3,5-trifluoro-2,5-dimethyl-6-oxopiperidin-2-yl)phenyl)carbamate

Product 1

HCID 118337835tert-butyl (4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamateYield 52.6%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

Tert-butyl (4-fluoro-3-((2R)-3,3,5-trifluoro-2,5-dimethyl-6-oxopiperidin-2-yl)phenyl)carbamate (2.1 g, 5.38 mmol) (1:1.7 mixture of diastereomers) was placed in a round bottom flask and dissolved in toluene (60 ml) (dried over 4 Å MS). Argon was bubbled through the reaction for 10 min followed by addition of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) (2.18 g, 5.38 mmol). The reaction was carefully evacuated and backfilled with argon (×3). The suspension was heated to 80° C. The reaction was stirred at this temperature for 3 h 30 min. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The crude material was suspended in CHCl3 and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified using a CombiFlash system (120 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→80:20) to afford tert-butyl (4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate (1.15 g, 52.6% yield) (fast eluting isomer) LC-MS (m/z) 407.4 (MH+) tR=0.83 minutes (Method B) and tert-butyl (4-fluoro-3-((2R,5R)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate (0.816 g (60% purity), 22.4% yield) (slow eluting isomer) LC-MS (m/z) 407.4 (MH+) tR=0.82 minutes (Method B).

Workup

  1. customArgon was bubbled through the reaction for 10 min
  2. customThe reaction was carefully evacuated
  3. temperatureto cool to room temperature
  4. concentrationconcentrated under reduced pressure
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customthe crude material was purified
  8. washa CombiFlash system (120 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→80:20)

Sources & evidence

ORD record
ord-c3a192b495514068bf1ac7b01216e012
Source dataset
uspto-grants-2016_05
Patent number
US09353084B2

Reaction notes

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