Potassium Carbonate → (+/-)-6-Chloro-5-(4-(tetrahydrofuran-3-yl)phenyl)-1H-indazole-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (110 mg, 0.32 mmol), oven dried potassium acetate (140 mg, 1.42 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (27.0 mg, 0.033 mmol), and (±)-3-(4-bromophenyl)tetrahydrofuran (70.0 mg, 0.31 mmol) in 1,4-dioxane (3.1 mL) was degassed with N2 for 10 minutes, and subjected to microwave irradiation at 115° C. for 1 hour. The cooled reaction mixture was filtered through cotton and concentrated in vacuo to give a dark solid. To the dark solid was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (75.0 mg, 0.270 mmol), 2 N aqueous potassium carbonate solution (0.543 mL, 1.09 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (22.0 mg, 0.027 mmol). The reaction mixture was diluted with degassed toluene (0.8 mL) and EtOH (0.8 mL), and heated at 100° C. for 1.5 hours in a sealed tube. The cooled reaction mixture was concentrated in vacuo, and the residue was partitioned between 0.5 N HCl (15 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting brown solid was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 10.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to give the title compound (9.6 mg, 10% yield). MS (ES+) 343.1 (M+H)+. Retention time=2.63 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Provenance & Evidence