Hydrochloric Acid → 2-(3-Methoxy-phenyl)-2-methyl-pyrrolidine

Participants

Reaction Conditions

Reaction Steps

Add boron trifluoride diethyl etherate (1.34 g, 9.42 mmol) dropwise over 5 min to a −78° C. solution of 5-(3-methoxy-phenyl)-3,4-dihydro-2H-pyrrole (1.50 g, 8.56 mmol) in tetrahydrofuran (60 mL). After stirring for 45 min, add methyllithium (1.6 M in diethyl ether, 10.70 mL, 17.10 mmol) dropwise over 10 min. After stirring the bright yellow reaction mixture for 2.5 h, warm the reaction mixture slowly to 0° C. After 1.5 h replace the dry ice/acetone cooling bath with an ice bath. After 15 min, quench the reaction using water (50 mL) and saturated aqueous ammonium chloride (50 mL) and adjust the pH to about 11-12 using aqueous 2 M sodium hydroxide. Extract the aqueous layer with 9:1 methylene chloride/chloroform (3×200 mL) and dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain an orange oil. Redissolve the crude oil in methylene chloride (200 mL) and add aqueous 2 M hydrochloric acid (200 mL). Separate the layers and extract the aqueous layer with additional methylene chloride (100 mL) and discard the combined organic layers. Adjust the resulting aqueous layer to a pH of 14 using aqueous 2 M sodium hydroxide (about 250 mL), extract with 1:1 methylene chloride/chloroform (2×250 mL), dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain an orange oil (1.30 g). Purify the oil by flash chromatography eluting with a gradient of methylene chloride/90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide (4:1 to 1:1) to obtain the title compound (650 mg, 40%) as a light yellow oil. MS (APCI+): 192 [Cl2H17NO+H]+; 1H NMR (300 MHz, CDCl3): δ 7.24 (symmetrical m, 1H), 7.09-7.03 (m, 2H), 6.75 (ddd, J=8.1, 2.6, 0.9 Hz, 1H), 3.81 (s, 3H), 3.16-2.94 (symmetrical m, 2H), 2.14-2.01 (m, 1H), 1.94-1.67 (m, 4H), 1.42 (s, 3H).

Provenance & Evidence