Formic Acid → 8-Bromo-6-chloro-1,1-dimethyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine

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Reaction Conditions

Reaction Steps

A mixture of the product of step E (75 mg, 0.27 mmol), acetone (3 mL) and titanium tetra-isopropoxide (93 mg, 0.32 mmol), was heated at 90° C. under an argon atmosphere. After 3 h, the reaction mixture was cooled to 0° C. and a solution of formic acid (1.03 mL, 27.3 mmol) and acetic anhydride (4.21 mL, 54.6 mmol) was added. After heating the reaction mixture to 90° C. for 2 h, trifluoroacetic acid was added and the reaction was maintained at 90° C. for 16 h. The reaction mixture was cooled to ambient temperature, quenched with methanol (10 mL) and diluted with 20% methanol/dichloromethane (120 mL). The mixture was passed through a short silica gel column and the filtrate concentrated in vacuo. The residue was dissolved in ethanol (6 mL) and 20% aqueous sodium hydroxide (6 mL) was added. After refluxing for 15 h, the reaction mixture was cooled, diluted with water (30 mL), and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 95:5 dichloromethane/methanol) providing 8-bromo-6-chloro-1,1-dimethyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (45 mg, 52%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.49 (d, J=2.0 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 3.24 (t, J=5.6 Hz, 2H), 2.77 (t, J=5.6 Hz, 2H), 1.49 (s, 6H).

Provenance & Evidence