2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → HCID 56932319, compound

HRID 1972430Notes

Reaction equation

HRID 1972430 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.[CH2:18]([C@@H:25]1[NH:30][CH2:29][CH2:28][N:27]([S:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)(=[O:33])=[O:32])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>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>[CH2:18]([C@H:25]1[CH2:26][N:27]([S:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:33])[CH2:28][CH2:29][N:30]1[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)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1

Participants

7

Reactant 4

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 232335702-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-olHCID 23676156Sodium t-butoxideHCID 66582712HCID 66582712, compound

Product 1

HCID 56932319HCID 56932319, compoundYield 13.7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.22 g, 0.68 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), (3S)-3-benzyl-1-(2-thiophenylsulfonyl)piperazine (0.20 g, 0.62 mmol), sodium tert-butoxide (0.19 g, 1.9 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.058 g, 0.12 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.057 g, 0.062 mmol, Strem Chemical Inc, Newburyport, Mass.), and toluene (2.5 mL) were added to a high-pressure reaction vessel under a nitrogen atmosphere. The vessel was sealed and was heated at 100° C. for 29 h. Then the mixture was allowed to cool to room temperature and then partitioned between EtOAc (15 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated and the organic material was washed sequentially with saturated aqueous sodium bicarbonate (25 mL) and brine (15 mL), dried (Na2SO4) and filtered. The filtrate was concentrated, and the solution, and the volatiles were removed in vacuo. The residue was subjected purified via column chromatography using silica gel (twice, 100% CH2Cl2, then 25% EtOAc in hexanes) to give of 2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.048 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.72-7.54 (m, 4H), 7.33-7.14 (m, 6H), 6.94 (d, J=7.2 Hz, 2H), 4.04 (d, J=8.2 Hz, 1H), 3.91 (d, J=9.4 Hz, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.54 (d, J=11.2 Hz, 1H), 3.42 (t, J=10.9 Hz, 1H), 3.31 (br. s., 1H), 3.21 (t, J=11.7 Hz, 1H), 2.67-2.48 (m, 3H); m/z (ESI, +ve ion) 565.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.308 μM; GK-GKRP EC50 (LC MS/MS)=0.772 μM.

Workup

  1. customThe vessel was sealed
  2. temperatureto cool to room temperature
  3. custompartitioned between EtOAc (15 mL) and saturated aqueous sodium bicarbonate (10 mL)
  4. customThe layers were separated
  5. washthe organic material was washed sequentially with saturated aqueous sodium bicarbonate (25 mL) and brine (15 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationThe filtrate was concentrated
  9. customthe solution, and the volatiles were removed in vacuo
  10. custompurified via column chromatography

Sources & evidence

ORD record
ord-793c54a9753e497fb1d90d6596285f63
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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