Formic Acid → HCID 21904688, compound

Participants

Reaction Conditions

Reaction Steps

Pentafluorophenol (852 mg, 4.64 mmol) was dissolved in diethyl ether (15 mL) and the solution cooled to 0° C. Formic acid (209 μL, 5.56 mol) was added followed by DCCl (956 mg, 4.64 mmol) and the mixture was stirred for 10 min. The white suspension was filtered off and the filtrate was cooled to 0° C. and treated with a solution of the product from Example 1 (640 mg, 2.32 mmol) in DCM (10 mL) and triethylamine (323 μL, 2.32 mmol). The resulting reaction mixture was stirred at room temperature for 6 h. The solvents were then removed under reduced pressure and the residue was basified with water (10 mL)/880 NH3 (1 mL) and extracted with DCM (4×15 mL). The combined organic extracts were dried (MgSO4) and evaporated to an oily-solid residue (844 mg, ca. 100%); δH (CDCl3, 400 MHz) 2.42 (3H, s), 3.87 (3H, s), 4.55 (2H, s), 5.98 (1H, brs), 6.50 (1H, dd), 6.59 (1H, d), 7.17 (1H, d), 7.31 (1H, d), 8.21 (1H, s), 8.29 (1H, s), 8.38 (1H, d). This material was carried on directly to the reduction stage without further purification. The crude formamide was dissolved in THF (10 mL) and treated with borane-THF complex (1M in THF, 7 mL, 7 mmol). The resulting pale yellow solution was heated at reflux under nitrogen for 3.5 h. After cooling to room temperature, the reaction was quenched by the careful addition of 6 M HCl (7 mL) and the mixture was subsequently heated to reflux for 3 h. Most of the THF was removed by evaporation and the resulting aqueous solution was washed with diethyl ether (2×10 mL) and then basified by the addition of 880 NH3. Extraction with DCM (4×10 mL) followed by drying of the combined extracts (MgSO4) and evaporation afforded a clear oil. Purification by flash chromatography [SiO2; DCM/MeOH/880 NH3 (95:5:0.5)] gave the desired compound as a colourless oil. A portion of this material (300 mg) was dissolved in DCM (5 mL) and treated with 1M HCl in diethyl ether (5 mL) and the resulting mixture was evaporated to dryness twice from DCM. The resulting yellow oil was dissolved in DCM (5 mL) and treated with diethyl ether dropwise to induce precipitation. The solvents were removed under reduced pressure and the resulting pale yellow solid was dried under vacuum (345 mg); Bis HCl salt: δH (CD3OD, 400 MHz) 2.39 (3H, s), 2.87 (3H, s), 3.85 (3H, s), 4.58 (2H, s), 6.87 (1H, dd), 6.95 (1H, d), 7.29 (1H, d), 8.06 (1H, d), 8.28 (1H, s), 8.58 (1H, d); MS m/z (TS+) 291 (MH+).

Provenance & Evidence