m-Fluorobenzenethiol → (S)-3-[4-(3-fluoro-phenylsulfanyl)-2-hydroxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 503943Notes

Reaction equation

HRID 503943 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[C:60]([O:64][C:65]([N:67]1[CH2:71][CH2:70][C@@H:69]([C:72]2[CH:77]=[CH:76][C:75](Br)=[CH:74][C:73]=2[OH:79])[CH2:68]1)=[O:66])([CH3:63])([CH3:62])[CH3:61].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.[Cl-].[Na+].O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:60]([O:64][C:65]([N:67]1[CH2:71][CH2:70][C@@H:69]([C:72]2[CH:77]=[CH:76][C:75]([S:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:74][C:73]=2[OH:79])[CH2:68]1)=[O:66])([CH3:63])([CH3:61])[CH3:62]

Participants

9

Reactant 5

HCID 75710m-FluorobenzenethiolHCID 81531DiisopropylethylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 59428430(S)-3-(4-bromo-2-hydroxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 86586342KHSO4 Na2SO4

Product 1

HCID 59428396(S)-3-[4-(3-fluoro-phenylsulfanyl)-2-hydroxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 70.5%

Reagents, catalysts & solvents 3

HCID 9832798Tris(dibenzylideneacetone) dipalladiumCatalystHCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
5 °C

Procedure

3-Fluorothiophenol (58 μL, 0.681 mmol), Tris(dibenzylideneacetone) dipalladium(0) (77.4 mg, 0.085 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (97.4 mg, 0.170 mmol) and DIPEA (0.156 mL, 1.71 mmol) were added to a solution of (S)-3-(4-bromo-2-hydroxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (233 mg, 0.681 mmol) in 1,4-dioxane (4.6 mL). The reaction mixture was heated at reflux for 18 hours, then cooled to 5° C. and a solution of 10% KHSO4/Na2SO4 was added, followed by brine. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered through a celite pad, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/acetone, 9/1) to give 187 mg (70% yield) of (S)-3-[4-(3-fluoro-phenylsulfanyl)-2-hydroxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux for 18 hours
  3. extractionThe mixture was extracted with EtOAc
  4. washthe combined organic extracts were washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered through a celite pad
  7. customevaporated under reduced pressure
  8. customThe resulting crude material was purified via flash chromatography (hexane/acetone, 9/1)

Sources & evidence

ORD record
ord-7eaa92bf92ab4699bd2b72ac791c34ba
Source dataset
uspto-grants-2010_08
Patent number
US07776910B2

Reaction notes

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