3-methyl-1,4-oxazepan-5-one

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (95%, 553 mg, 21.9 mmol, 1.15 equiv) was added to a solution of 3-methyl-1,4-oxazepan-5-one (4-2, 2.46 g, 19.0 mmol, 1 equiv) in DMF (40 mL) at 0° C. and the resulting mixture was stirred for 20 min. Benzyl bromide (2.49 mL, 20.9 mmol, 1.10 equiv) was added and the mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was partitioned between brine (100 mL) and ethyl acetate (2×100 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 5.05 (d, 1H,J=14.6 Hz), 4.17 (d, 1H,J=14.6 Hz), 4.00 (ddd, 1H,J=12.5, 6.1, 3.3 Hz), 3.80 (dd, 1H,J=12.8, 4.0 Hz), 3.56 (dd, 1H,J=12.5 Hz), 3.42 (d, 1H,J=12.8 Hz), 3.31 (m, 1H), 3.02 (ddd, 1H,J=15.0, 11.9, 3.4 Hz), 2.75 (ddd, 1H,J=16.2, 4.9, 1.2 Hz), 1.31 (d, 3H,J=7.3 Hz). LRMS m/z (M+H) 220.3 found, 220.1 required. stirred for 20 h The reaction mixture was partitioned between brine (100 mL) and ethyl acetate (2×100 mL) the combined organic layers were dried over sodium sulfate concentrated The residue was purified by flash column chromatography (20% EtOAc in hexanes initially

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methanesulfonic acid (20 mL) was added to a solution of 3-methyltetrahydro-4H-pyran-4-one (4-1, prepared by the method of Smith, A. B. et al. J. Am. Chem. Soc. 1991, 113, 2071, 3.00 g, 26.3 mmol, 1 equiv) in DME (30 mL) at −40° C. Sodium azide (5.13 g, 79.0 mmol, 3.00 equiv) was added in four equal portions over 30 min as cooling was maintained. The cold bath was then removed and the reaction mixture was warmed to 23° C. and stirred for 20 h. The mixture was diluted with DME (20 mL) and basified to pH 9 with concentrated aqueous ammonium hydroxide solution. The resulting mixture was partitioned between brine (200 mL) and a solution of 10% n-propanol in ethyl actetate (2×400 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 3-methyl-1,4-oxazepan-5-one (4-2) as a pasty white solid. 1H NMR (300 MHz, CDCl3) δ 5.73 (br s, 1H), 3.97 (ddd, 1H,J=12.4, 5.6, 2.8 Hz), 3.83 (d, 1H,J=12.2 Hz), 3.76 (m, 1H), 3.66 (dd, 1H,J=12.4, 10.8 Hz), 3.35 (dd, 1H, J=12.2, 8.2 Hz), 2.89 (ddd, 1H,J=15.8, 10.8, 2.8 Hz), 2.54 (dd, 1H,J=15.8, 5.6 Hz), 1.15 (d, 3H,J=7.1 Hz). prepared by the method of Smith at −40° C as cooling was maintained The cold bath was then removed The mixture was diluted with DME (20 mL) The resulting mixture was partitioned between brine (200 mL) The combined organic layers were dried over sodium sulfate concentrated

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (95%, 553 mg, 21.9 mmol, 1.15 equiv) was added to a solution of 3-methyl-1,4-oxazepan-5-one (4-2, 2.46 g, 19.0 mmol, 1 equiv) in DMF (40 mL) at 0° C. and the resulting mixture was stirred for 20 min. Benzyl bromide (2.49 mL, 20.9 mmol, 1.10 equiv) was added and the mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was partitioned between brine (100 mL) and ethyl acetate (2×100 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 5.05 (d, 1H,J=14.6 Hz), 4.17 (d, 1H,J=14.6 Hz), 4.00 (ddd, 1H,J=12.5, 6.1, 3.3 Hz), 3.80 (dd, 1H,J=12.8, 4.0 Hz), 3.56 (dd, 1H,J=12.5 Hz), 3.42 (d, 1H,J=12.8 Hz), 3.31 (m, 1H), 3.02 (ddd, 1H,J=15.0, 11.9, 3.4 Hz), 2.75 (ddd, 1H,J=16.2, 4.9, 1.2 Hz), 1.31 (d, 3H,J=7.3 Hz). LRMS m/z (M+H) 220.3 found, 220.1 required. stirred for 20 h The reaction mixture was partitioned between brine (100 mL) and ethyl acetate (2×100 mL) the combined organic layers were dried over sodium sulfate concentrated The residue was purified by flash column chromatography (20% EtOAc in hexanes initially

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methanesulfonic acid (20 mL) was added to a solution of 3-methyltetrahydro-4H-pyran-4-one (4-1, prepared by the method of Smith, A. B. et al. J. Am. Chem. Soc. 1991, 113, 2071, 3.00 g, 26.3 mmol, 1 equiv) in DME (30 mL) at −40° C. Sodium azide (5.13 g, 79.0 mmol, 3.00 equiv) was added in four equal portions over 30 min as cooling was maintained. The cold bath was then removed and the reaction mixture was warmed to 23° C. and stirred for 20 h. The mixture was diluted with DME (20 mL) and basified to pH 9 with concentrated aqueous ammonium hydroxide solution. The resulting mixture was partitioned between brine (200 mL) and a solution of 10% n-propanol in ethyl actetate (2×400 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 3-methyl-1,4-oxazepan-5-one (4-2) as a pasty white solid. 1H NMR (300 MHz, CDCl3) δ 5.73 (br s, 1H), 3.97 (ddd, 1H,J=12.4, 5.6, 2.8 Hz), 3.83 (d, 1H,J=12.2 Hz), 3.76 (m, 1H), 3.66 (dd, 1H,J=12.4, 10.8 Hz), 3.35 (dd, 1H, J=12.2, 8.2 Hz), 2.89 (ddd, 1H,J=15.8, 10.8, 2.8 Hz), 2.54 (dd, 1H,J=15.8, 5.6 Hz), 1.15 (d, 3H,J=7.1 Hz). prepared by the method of Smith at −40° C as cooling was maintained The cold bath was then removed The mixture was diluted with DME (20 mL) The resulting mixture was partitioned between brine (200 mL) The combined organic layers were dried over sodium sulfate concentrated