Methyl iodide → HCID 66748117, compound

Participants

Reaction Conditions

Reaction Steps

A 1 L flask was charged with a big egg-shape stirring bar and ethyl 4-cyano-5-morpholin-4-yl-3-(2-naphthylmethyl)thiophene-2-carboxylate (14.5 g, 35.7 mmol). To the flask was added N,N-dimethylformamide (240 mL) and the mixture was evacuated and purged with nitrogen (×3). To the flask was added tetrahydrofuran (60 mL), and the mixture was stirred until it became a clear yellow solution. The solution was cooled to ˜−25° C. in a dry ice-acetone bath (the temperature was actively controlled by slow addition of dry ice between −30˜−40° C.). 1 M of Potassium tert-butoxide in tetrahydrofuran (42.8 mL) was added dropwise over 3 min. The mixture turned deep purple immediately. After the addition the mixture was stirred for 10 min at this temperature. Methyl iodide (11.1 mL, 178 mmol) was added over 1 min. By the end of addition the mixture turned light red. After stirring the resulting mixture at 0° C. for 10 min, the reaction was quenched by addition of 10 mL of water. All volatiles were removed under reduced pressure and the resulting mixture was distributed between brine and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with 10% LiCl (aq) soln (×3), then brine, dried, and concentrated to provide a yellow syrup. Purification on a silica gel column (gradient elution 5-20% EtOAc/hexanes) provided Ethyl 4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylate as a white solid (11.8 g, 78.7% yield). LCMS: (AA) ES+ 421; 1H NMR (400 MHz, CDCl3) δ 7.90-7.82 (m, 2H), 7.82-7.70 (dd, J=15.4, 8.1 Hz, 2H), 7.50-7.37 (m, 3H), 5.82-5.67 (q, J=7.3 Hz, 1H), 4.40-4.25 (qd, J=6.1, 5.0, 3.1 Hz, 2H), 3.86-3.72 (t, J=4.8 Hz, 4H), 3.54-3.44 (t, J=4.8 Hz, 4H), 1.95-1.85 (d, J=7.3 Hz, 3H), 1.42-1.31 (t, J=7.1 Hz, 3H).

Provenance & Evidence