Pyridine → [5-(Trifluoromethyl)-1-benzothiophen-2-yl]methanol

Participants

Reaction Conditions

Reaction Steps

Pyridine (0.37 ml, 4.72 mmol, 1.5 equiv.) and subsequently cyanuric fluoride (0.53 ml, 6.3 mmol, 2 equiv.) were added to a stirred solution of commercially available 5-(trifluoromethyl)-1-benzothiophene-2-carboxylic acid (776 mg, 3.15 mmol, 1 equiv.) in CH2Cl2 (16 ml), kept under N2, at −20 to −10° C. Precipitation of cyanuric acid occurred and increased gradually as the reaction proceeded. After the mixture was stirred at −20 to −10° C. for 2 h, ice-cold water was added along with 100 ml CH2Cl2. Undissolved solids were filtered off; from the filtrate, the organic phase was separated and the aqueous layer was extracted once more with CH2Cl2 (50 ml). The combined organic layers were washed with ice-cold water (50 ml), dried (Na2SO4) and concentrated under reduced pressure to a small volume (15 ml). NaBH4 (240 mg, 6.3 mmol, 2 equiv.) was added in one portion, and MeOH (6.5 ml) was then added, dropwise, over 15 min at r.t. The reaction mixture was neutralised with 1N H2SO4, and the organic solvents were evaporated under reduced pressure. The residue was taken-up in EtOAc (80 ml) and water (40 ml); the organic layer was separated, and the aqueous layer was extracted with EtOAc (2×60 ml). The combined organic layers were washed with 1N H2SO4 and brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica, using EtOAc/hexane (10-20% gradient) as eluent, to give 400 mg (54.6% yield) of the required product as a white solid. HPLC-MS (method 1) gave one peak with Rt=4.02 min, but no ionization.

Provenance & Evidence