2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → HCID 86670307, compound

HRID 1972348Notes

Reaction equation

HRID 1972348 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.[CH3:19][C@H:20]1[CH2:25][N:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:23][CH2:22][NH:21]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O.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].C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:24]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH2:25][C@@H:20]2[CH3:19])=[CH:3][CH:4]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]

Participants

8

Reactant 4

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 232335702-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-olHCID 23676156Sodium t-butoxideHCID 66582415HCID 66582415, compound

Product 1

HCID 86670307HCID 86670307, compoundYield 17.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A 20 mL vial was charged with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.52 g, 4.70 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), (S)-2-methyl-4-(phenylsulfonyl)piperazine hydrochloride (1.00 g, 3.61 mmol), sodium tert-butoxide (1.13 g, 11.7 mmol), and 10 mL of anhydrous toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.051 g, 0.11 mmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (0.033 g, 0.036 mmol, Strem Chemical Inc, Newburyport, Mass.). The vial was sealed and the mixture was heated at 100° C. for 12 h. After that time, the reaction was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The organics were dried (MgSO4) and concentrated to give an oil that was purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.310 g). 1H NMR (400 MHz, CD3OD) δ 7.83-7.74 (m, 2H), 7.72-7.60 (m, 3H), 7.53 (d, J=8.8 Hz, 2H), 6.94 (d, J=9.2 Hz, 2H), 4.18-4.02 (m, 1H), 3.70 (dd, J=2.4, 11.2 Hz, 1H), 3.56-3.36 (m, 2H), 3.20 (dt, J=3.4, 11.8 Hz, 1H), 2.69 (dd, J=3.4, 11.4 Hz, 1H), 2.53 (dt, J=3.5, 11.2 Hz, 1H), 1.13 (d, J=6.5 Hz, 3H). M/Z (ESI, +ve ion) 483.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.821 μM; GK-GKRP EC50 (LC MS/MS)=0.884 μM.

Workup

  1. customThe vial was sealed
  2. extractionextracted with EtOAc (2×20 mL)
  3. dry with materialThe organics were dried (MgSO4)
  4. concentrationconcentrated
  5. customto give an oil that
  6. customwas purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-bff3bd47ca70481c8f262f4044473131
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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