ethyl 2-(oxolan-3-yl)propanoate

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N,N-diisopropylamine (1.28 mL, 9.1 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to −30° C. before adding n-butyllithium (3.22 mL, 8.08 mmol, 2.5 M in hexanes). The reaction mixture was stirred at −30° C. for 15 minutes before adding a solution of 2-(tetrahydro-furan-3-yl)-propionic acid ethyl ester (0.87 g, 5.05 mmol) in tetrahydrofuran (6 mL) dropwise over 3 minutes. The reaction mixture was stirred for a further 15 minutes at −30° C. before adding dibromobis(tributylphosphine)palladium(II) (40 mg, 50 μmol) and then a solution of vinylbromide (9.0 mL, 9.0 mmol, 1 M in tetrahydrofuran). The reaction mixture was stirred at −30° C. for 30 minutes then warmed to room temperature for 18 h. The reaction mixture was treated with hydrochloric acid (2 M, 20 mL). The mixture was extracted with diethyl ether (3×20 mL). The organics extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/diethyl ether 3:2 to yield the title product (237 mg, 24%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.14-1.30 (m, 6H), 1.61-1.75 (m, 1H), 1.84-1.99 (m, 1H), 2.68-2.82 (m, 1H), 3.52-3.95 (m, 4H), 4.10-4.21 (m, 2H), 5.09-5.23 (m, 2H), 5.95-6.07 (m, 1H). LCMS (m/z) 199.2 [M+H], Tr=2.17 min. The reaction mixture was stirred for a further 15 minutes at −30° C. The reaction mixture was stirred at −30° C. for 30 minutes then warmed to room temperature for 18 h The mixture was extracted with diethyl ether (3×20 mL) The organics extract was dried over anhydrous sodium sulfate filtered evaporated The residue was purified by silica gel chromatography

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of N,N-diisopropylamine (2.38 mL, 17.0 mmol) in anhydrous tetrahydrofuran (40 mL) was cooled to −20° C. before adding n-butyllithium (6.3 mL, 15.8 mmol, 2.5 M in hexanes). The reaction was allowed to warm to −10° C. for 10 minutes then cooled to −78° C. A solution of (tetrahydro-furan-3-yl)-acetic acid ethyl ester (1.23 g, 7.77 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was stirred for 2.5 h at −78° C. and then methyl iodide (3.92 mL, 63.2 mmol) was added. The reaction was stirred for 15 h gradually warming to room temperature. The reaction was quenched with a saturated aqueous ammonium chloride solution (60 mL) and then extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to yield the title product (0.87 g, 65%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.13-1.30 (m, 6H), 1.51-1.69 (m, 1H), 1.96-2.11 (m, 1H), 2.29-2.51 (m, 2H), 3.39-3.48 (m, 1H), 3.67-3.80 (m, 1H), 3.81-3.95 (m, 2H), 4.08-4.20 (m, 2H). then cooled to −78° C The reaction was stirred for 15 h gradually warming to room temperature The reaction was quenched with a saturated aqueous ammonium chloride solution (60 mL) extracted with ethyl acetate (3×30 mL) dried over anhydrous sodium sulfate filtered evaporated The residue was purified by silica gel chromatography

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of N,N-diisopropylamine (2.38 mL, 17.0 mmol) in anhydrous tetrahydrofuran (40 mL) was cooled to −20° C. before adding n-butyllithium (6.3 mL, 15.8 mmol, 2.5 M in hexanes). The reaction was allowed to warm to −10° C. for 10 minutes then cooled to −78° C. A solution of (tetrahydro-furan-3-yl)-acetic acid ethyl ester (1.23 g, 7.77 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was stirred for 2.5 h at −78° C. and then methyl iodide (3.92 mL, 63.2 mmol) was added. The reaction was stirred for 15 h gradually warming to room temperature. The reaction was quenched with a saturated aqueous ammonium chloride solution (60 mL) and then extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to yield the title product (0.87 g, 65%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.13-1.30 (m, 6H), 1.51-1.69 (m, 1H), 1.96-2.11 (m, 1H), 2.29-2.51 (m, 2H), 3.39-3.48 (m, 1H), 3.67-3.80 (m, 1H), 3.81-3.95 (m, 2H), 4.08-4.20 (m, 2H). then cooled to −78° C The reaction was stirred for 15 h gradually warming to room temperature The reaction was quenched with a saturated aqueous ammonium chloride solution (60 mL) extracted with ethyl acetate (3×30 mL) dried over anhydrous sodium sulfate filtered evaporated The residue was purified by silica gel chromatography