Hydrochloric Acid → 6-Methoxy-1-methyl-1-trifluoromethylisochroman

Participants

Reaction Conditions

Reaction Steps

To a solution of 1,1,1-trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-ol (5.00 g, 18.9 mmol) in dichloromethane (30 mL) was added triethylamine (9.20 mL, 66.3 mmol). The solution was cooled to 0° C. and methanesulfonyl chloride (1.61 mL, 20.8 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred 12 hours. The formation of methanesulfonic acid 2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl ester is rapid and its disappearance was monitored by HPLC (retention time=4.5 minutes, Zorbax Rx-C6 column 4.6×150 mm, 40° C., 50% CH3CN/50% (0.2% Et3N, 0.1% H3PO4 aqueous pH=3.2 buffer), 1 mL/min). At the end of the reaction, the mixture was poured into 1N aqueous hydrochloric acid (30 mL) and was extracted with dichloromethane (20 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman as an oil (3.40 g, 73%). 1H NMR (300 MHz, CDCl3) δ1.69 (s, 3), 2.85-2.90 (m, 2), 3.85 (s, 3), 3.90-3.98 (m, 1), 4.14-4.21 (m, 1), 6.72 (d, 1, J=2.6), 6.85 (dd, 1, J=8.7, 2.6), 7.31 (d, 1, J=8.7). 13C NMR (100 MHz, CDCl3) δ23.25, 29.42, 55.19, 61.37, 76.10 (q, J=27.4), 112.84, 113.43, 124.85, 125.96 (q, J=289), 127.86, 136.49, 158.98. IR 2946, 2839, 1738, 1611, 1505, 1162, 1137, 1101 cm−1. Analysis calculated for C12H13F3O2: C, 58.54; H, 5.32. Found: C, 58.27; H, 5.35.

Provenance & Evidence