Trifluoroacetic acid → 3-(2,4-Dichloro-phenyl)-1,1,1-trifluoro-2-(5-fluoro-1H-indol-3-yl)-butan-2-ol

Participants

Reaction Steps

To a solution of crude 3-[2-(2,4-dichloro-phenyl)-propionyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (81 mg) in tetrahydrofuran (0.8 ml) (trifluoromethyl)-trimethylsilane (2M in tetrahydrofuran, 0.23 ml) and tetrabutylammonium difluorotriphenylsilicate (20 mg) were added at 0° C. After being stirred at rt for 3 h, trifluoroacetic acid (127 mg) was added at 0° C. and stirred overnight. No deprotection was observed, so the mixture was neutralized with aq. 2M Na2CO3 solution and extracted with EtOAc. The combined organic layers were washed with water and dried over MgSO4. After evaporation of the solvent, the residue was dissolved in CH2Cl2 (0.8 mL) and trifluoroacetic acid was added at 0° C. After being stirred for 1 h at 0° C. and at room temperature for 8 h, the reaction mixture was poured into ice water, neutralized with aq. 2M Na2CO3 solution and extracted with CH2Cl2. The organic phase was washed with water and aq. sat. NaCl solution, and dried over MgSO4. MS: silylated product still present, the crude product was dissolved in 0.5 mL tetrahydrofuran and a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran) was added at 0° C. After being stirred at room temperature for 1.5 h, the reaction mixture was poured into water, and extracted with EtOAc. The combined organic layers were washed with water and aq. sat. NaCl, and dried over MgSO4. The product was purified by preparative TLC (cyclohexane/EtOAc 2:1) to give 17.9 mg of the title product as colorless oil. MS (m/e, ISP neg. ion)=404.4 [M−H+].

Provenance & Evidence