Triethylamine → 1-Chloro-6-methoxyisoquinoline

Participants

Reaction Conditions

Reaction Steps

1-Chloro-6-methoxy-isoquinoline was prepared according to the following procedure. To a solution of 3-methoxy cinnamic acid (25 g, 140.3 mmol) and triethylamine (39.1 mL, 280.6 mmol) in THF (200 mL) was added ethyl chloroformate (20 ml, 210 mmol) dropwise at 0° C. After stirring at this temperature for 1 hour, aqueous NaN3 (14.7 g, 226 mmol in 80 mL H2O) was added dropwise and the reaction mixture was stirred for 16 hours at ambient temperature. Water (220 mL) was added to the mixture and the volatiles were removed in vacuo. The resulting slurry was extracted with toluene (3×110 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated. The dried solution was added dropwise to a heated solution of diphenylmethane (120 mL) and tributylamine (68 mL) at 190° C. The toluene was distilled off during the addition. After complete addition, the reaction temperature was raised to 210° C. for 2 hours. Upon cooling via an ice bath, the precipitated product was collected by filtration, washed with hexanes, and dried to yield the desired product as an off-white solid (14.04 g, 57%): LCMS found 176.1 [M+H]+. 6-Methoxy-2H-isoquinolin-1-one (14.04 g, 80.15 mmol) in POCl3 (30.5 ml) was heated to gentle reflux for 1 hour and the mixture was then concentrated in vacuo. The residue was poured into ice water and brought to pH 10 by the addition of 10 M NaOH. The resulting mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford 13.31 g (86%) of the desired 1-chloro-6-methoxy-isoquinoline intermediate as a white solid. LCMS found 194.19 [M+H]+.

Provenance & Evidence