Reaction Steps
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.
