2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 1,1,1,3,3,3-Hexafluoro-2-(4-(2-(3-methoxybenzyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-2-propanol

HRID 1972551Notes

Reaction equation

HRID 1972551 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[NH:12][CH2:11][CH2:10][N:9]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:8]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].Br[C:65]1[CH:70]=[CH:69][C:68]([C:71]([OH:80])([C:76]([F:79])([F:78])[F:77])[C:72]([F:75])([F:74])[F:73])=[CH:67][CH:66]=1>C1(C)C=CC=CC=1.[NH4+].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:73][C:72]([F:74])([F:75])[C:71]([C:68]1[CH:67]=[CH:66][C:65]([N:12]2[CH2:11][CH2:10][N:9]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH2:8][CH:7]2[CH2:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:70][CH:69]=1)([OH:80])[C:76]([F:77])([F:79])[F:78]

Participants

8

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 232335702-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-olHCID 23676156Sodium t-butoxideHCID 66583112HCID 66583112, compound

Product 1

HCID 866703961,1,1,3,3,3-Hexafluoro-2-(4-(2-(3-methoxybenzyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-2-propanolYield 49.3%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
100 °C

Procedure

To a 50-mL round-bottomed flask was added 3-(3-methoxybenzyl)-1-(thiophen-2-ylsulfonyl)piperazine (48 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (0) (6 mg, 6.81 μmol, Strem, Newburyport, Mass.), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (RuPhos) (13 mg, 0.027 mmol, Strem Chemicals, Newburyport, Mass.), sodium tert-butoxide (33 mg, 0.34 mmol) and 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (53 mg, 0.16 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009) in toluene (2 mL). The reaction mixture was stirred at 100° C. for 18 h. The mixture was cooled to room temperature and then diluted with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc in hexanes to give 1,1,1,3,3,3-hexafluoro-2-(4-(2-(3-methoxybenzyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-2-propanol (41 mg) (racemic mixture) as a colorless tar.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. extractionextracted with EtOAc (2×30 mL)
  3. extractionThe organic extract
  4. washwas washed with saturated NaCl (10 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationThe solution was filtered
  7. concentrationconcentrated in vacuo
  8. customto give the crude material as light-yellow oil
  9. customThe crude product was purified by silica gel chromatography
  10. washeluting with 20% EtOAc in hexanes

Sources & evidence

ORD record
ord-e521a7592e564b06b3876e01d43dcb3e
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

Loading…