4-(3-chloropropyl)oxane-4-carbonitrile

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

Procedure: A mixture of 4-(3-chloropropyl)-tetrahydro-2H-pyran-4-carbonitrile (1.83 g, 9.75 mmol) and NaI (3.0 g, 20 mmol) was stirred at ambient temperature for 1 h. To this reaction mixture was added 50% aqueous hydroxylamine (1 mL, 10.87 mmol) and stirred for three-days at ambient temperature. To this was added diethyl acetylenedicarboxylate (1.6 mL, 10 mmol) and stirred for 1 h. Then, the reaction mixture was diluted with EtOAc (100 mL) washed with water (50 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give yellow oil. Flash chromatography using 10-50% EtOAc/Hexanes afforded the title compound as pale yellow oil (0.627 g, 18%). 1H NMR (500 MHz, CDCl3) δ: HRMS (M+H) calcd for C17H27N2O5; found. 1H NMR (500 MHz, CDCl3) δ: 4.32-4.20 (2H, m), 4.14 (2H, q, J=7.0 Hz), 3.86 (1H, td, J=11.0, 2.7 Hz), 3.79-3.70 (3H, m), 3.52-3.46 (1H, m), 3.38-3.34 (1H, m), 3.26 (1H, d, JAB=16.2 Hz), 2.97 (1H, d, JAB=16.2 Hz), 2.06-1.89 (4H, m), 1.66-1.66 (2H, m), 1.60-1.53 (2H, m), 1.30 (3H, t, J=7.0 Hz), 1.24 (3H, t, J=7.0 Hz). stirred for three-days at ambient temperature stirred for 1 h washed with water (50 mL), brine (10 mL) dried (Na2SO4) filtered concentrated to give yellow oil

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1 M LiHMDS (25 mL, 25 mmol) in THF (10 mL) at −78° C. was added dropwise a solution of tetrahydro-2H-pyran-4-carbonitrile (2.23 g, 20 mmol) in THF (15 mL) over 10 minutes. After 40 min, 1-chloro-3-iodopropane (2.7 mL, 25 mmol) was added at once, stirred at −78° C. for 1 h and 4 h room temperature. Then the reaction mixture was diluted with ether (100 mL), washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated to give yellow oil which was purified by flash column chromatography using 10-30% EtOAc/Hexanes to afford the title compound as a colorless liquid (3.74 g, 99%). 1H NMR (500 MHz, CDCl3) δ: 3.97 (2H, dd, J=11.3, 3.7 Hz), 3.71 (2H, td, J=12.2, 1.8 Hz), 3.61 (2H, t, J=6.3 Hz), 2.05-1.98 (2H, m), 1.88 (2H, dd, J=13.4, 1.8 Hz), 1.77-1.74 (2H, m), 1.65-1.59 (2H, m). washed with water (20 mL) and brine (20 mL) dried (Na2SO4) filtered concentrated to give yellow oil which was purified by flash column chromatography