1-Bromo-4-(phenylsulfonyl)benzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 30 grams (0.1 mole) of 4-bromophenyl phenyl sulfone in 500 ml. of tetrahydrofuran was cooled to -100° C. in a liquid nitrogen-toluene slush, and 42 ml. (0.1 mole) of 2.38 M n-butyl lithium in hexane was added, forming 4-phenylsulfonyl-phenyl lithium. After about 10 minutes, 9.5 grams (0.05 mole) of diethyl dichlorophosphoramide was added, and the reaction mixture was allowed to warm slowly to room temperature, and then to stand a room temperature for 18 hours, forming diethyl bis [4-(phenylsulfonyl)phenyl] phosphoramide. Next, 125 ml. of 6 M HCl was added, and the reaction mixture was heated under reflux for 4 hours to hydrolyze the phosphoramide group. The tetrahydrofuran was removed by distillation, and 7.5 grams of almost white solid, M.P. 115°-130° C., was collected by filtration. This solid was recrystallized from tetrahydrofuran to give 7 grams (28% yield) of the bis[4-(phenylsulfonyl)phenyl] phosphinic acid product, m.p. 155°-165° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 mL round-bottomed flask was charged with 4-bromobenzenesulfonyl chloride (10.00 g, 39.1 mmol, Sigma-Aldrich, St. Louis, Mo.), 100 mL of benzene and aluminum chloride (6.26 g, 47.0 mmol). After stirring at room temperature for 12 h, the mixture was diluted water (100 mL) and extracted with EtOAc (2×100 mL). The organic extracts were dried (MgSO4) and concentrated to give 1-bromo-4-(phenylsulfonyl)benzene (10.50 g) as a white solid. extracted with EtOAc (2×100 mL) The organic extracts were dried (MgSO4) concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100 mL pressure vessel was charged with 1-bromo-4-(phenylsulfonyl)benzene (1.00 g, 3.37 mmol, Example 17, step 1), 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-propanol (1.62 g, 4.37 mmol), potassium carbonate (1.40 g, 10.10 mmol), tetrakis(triphenylphosphine)palladium (0) (0.194 g, 0.168 mmol), 20 mL of 1,2-dimethoxyethane, and 5 mL of water. The vessel was sealed and the reaction was heated to 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL), separated, dried (MgSO4) and concentrated to give an oil. Purification via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) produced a yellow solid that was slurried with cold (0° C.) MeOH (25 mL) to give 1,1,1,3,3,3-hexafluoro-2-(4′-(phenylsulfonyl)-4-biphenylyl)-2-propanol (0.650 g). 1H NMR (400 MHz, CD3OD) δ 8.08-7.95 (m, 4H), 7.91-7.74 (m, 6H), 7.69-7.54 (m, 3H). m/z (ESI, +ve ion) 461.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=1.66 μM; GK-GKRP EC50 (LC MS/MS)=3.96 μM. The vessel was sealed After cooling to room temperature separated dried (MgSO4) concentrated to give an oil Purification via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) produced a yellow solid

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 199 μl of bromobenzene (1.88 mmol) and 361 μl of benzenesulphonyl chloride (2.83 mmol) in 4 ml of trifluoroacetic acid there are added, in succession, 83 mg of indium chloride (0.376 mmol) and then, dropwise, 25 μl of trifluoromethanesulphonic acid. The reaction mixture is stirred for 2 hours at 70° C. and is then returned to ambient temperature and diluted with ice-cold water. After rendering alkaline to pH 10 by adding concentrated sodium hydroxide solution, the reaction mixture is extracted with CH2Cl2. The organic phases are collected, washed with saturated NaCl, dried (MgSO4) and evaporated under reduced pressure to yield the title product in the form of a white solid. is then returned to ambient temperature diluted with ice-cold water the reaction mixture is extracted with CH2Cl2 The organic phases are collected washed with saturated NaCl dried (MgSO4) evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir: