2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → HCID 66582315, compound

HRID 1972378Notes

Reaction equation

HRID 1972378 reaction equation
Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])=[O:8].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.Br[C:56]1[CH:61]=[CH:60][C:59]([C:62]([OH:68])([CH3:67])[C:63]([F:66])([F:65])[F:64])=[CH:58][CH:57]=1>C1(C)C=CC=CC=1.CO.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:64][C:63]([F:65])([F:66])[C:62]([C:59]1[CH:58]=[CH:57][C:56]([N:13]2[CH2:12][CH2:11][N:10]([S:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[CH2:15][CH2:14]2)=[CH:61][CH:60]=1)([OH:68])[CH3:67]

Participants

8

Reactant 4

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl2×HCID 23676156Sodium t-butoxideHCID 467434531032757-93-9HCID 583472902-(4-Bromophenyl)-1,1,1-trifluoropropan-2-ol

Product 1

HCID 66582315HCID 66582315, compound

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A 20 ml, vial was charged with 4-(2-thiophenylsulfonyl)piperazine hydrochloride (70 mg, 0.260 mmol), sodium tert-butoxide (45.7 mg, 0.476 mmol), tris(dibenzylideneacetone)dipalladium (0) (1.1 mg, 1.13 μmol, Strem Chemical Inc, Newburyport, Mass.), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.6 mg, 3.40 μmol, Strem Chemical Inc, Newburyport, Mass.) and 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (60.9 mg, 0.226 mmol, Example 27, step 1) in toluene (906 μL) was heated to 100° C. for 20 h. The reaction was then cooled to ambient temperature and additional tris(dibenzylideneacetone)dipalladium (0) (1.1 mg, 1.13 μmol, Strem Chemical Inc, Newburyport, Mass.) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (1.6 mg, 3.40 μmol, Strem Chemical Inc, Newburyport, Mass.) were added. The reaction was then heated to 100° C. for an additional 20 h. The reaction was cooled to ambient temperature and diluted with MeOH (2 mL). The reaction was loaded onto a 1 g AccuBOND II SCX cartridge, which was washed with MeOH (5 mL) and eluted with 2 N ammonia in MeOH (5 mL) to give the crude reaction mixture. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (10 g of silica gel, 5%-45% EtOAc in hexanes) to provide 1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two enantiomers.

Workup

  1. temperatureThe reaction was then cooled to ambient temperature
  2. temperatureThe reaction was then heated to 100° C. for an additional 20 h
  3. temperatureThe reaction was cooled to ambient temperature
  4. washwas washed with MeOH (5 mL)
  5. washeluted with 2 N ammonia in MeOH (5 mL)
  6. customto give the crude
  7. customreaction mixture
  8. customThe crude material was absorbed onto a plug of silica gel
  9. custompurified by column chromatography (10 g of silica gel, 5%-45% EtOAc in hexanes)

Sources & evidence

ORD record
ord-ca43454e8d2a4598a00c61d542194a50
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

Loading…