N-phenylmethoxymethanimine

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

Procedure: 37% Formaldehyde (11.7 mL) was added to a slurry of benzyloxyamine hydrochloride (25.0 g, 0.156 mole) in 50 mL H2O. NaOH (6.3 g) in 25 mL H2O was then added over 20 minutes. The temperature rose to 40°. After stirring 2 hours, the reaction mixture was extracted 1×100 mL and 2×25 mL of ether. The ether extracts were combined, washed 2×50 mL saturated NaHCO3 and then 2×50 mL brine, dried and evaporated to yield title product as an oil, 20.0 g, b.p. 195.5°. rose to 40° the reaction mixture was extracted 1×100 mL and 2×25 mL of ether washed 2×50 mL saturated NaHCO3 2×50 mL brine, dried evaporated

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

Procedure: 37% Formaldehyde (11.7 mL) was added to a slurry of benzyloxyamine hydrochloride (25.0 g, 0.156 mole) in 50 mL H2O. NaOH (6.3 g) in 25 mL H2O was then added over 20 minutes. The temperature rose to 40°. After stirring 2 hours, the reaction mixture was extracted 1×100 mL and 2×25 mL of ether. The ether extracts were combined, washed 2×50 mL saturated NaHCO3 and then 2×50 mL brine, dried and evaporated to yield title product as an oil, 20.0 g, b.p. 195.5°. rose to 40° the reaction mixture was extracted 1×100 mL and 2×25 mL of ether washed 2×50 mL saturated NaHCO3 2×50 mL brine, dried evaporated

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

Procedure: 37% Formaldehyde (11.7 mL) was added to a slurry of benzyloxyamine hydrochloride (25.0 g, 0.156 mole) in 50 mL H2O. NaOH (6.3 g) in 25 mL H2O was then added over 20 minutes. The temperature rose to 40°. After stirring 2 hours, the reaction mixture was extracted 1×100 mL and 2×25 mL of ether. The ether extracts were combined, washed 2×50 mL saturated NaHCO3 and then 2×50 mL brine, dried and evaporated to yield title product as an oil, 20.0 g b.p. 195.5°. rose to 40° the reaction mixture was extracted 1×100 mL and 2×25 mL of ether washed 2×50 mL saturated NaHCO3 2×50 mL brine, dried evaporated

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

Procedure: A 1M HCl/EtOH solution (50 mL) was added dropwise to the solution of formaldehyde O-benzyl-oxime (3.85 g, 28.48 mmol) in EtOH at 0° C. The mixture was stirred at room temperature for 1 hour, volatiles were removed in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated NaHCO3 solution (75 mL), water (75 mL), and dried over Na2SO4. The product was purified by flash column chromatography using gradient elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (7:1) to yield O-benzyl-N-methyl-hydroxylamine (1.72 g, 44%). 200 MHz 1H NMR (CDCl3, ppm) 7.40-7.27 (5H, m), 5.53 (1H, br s), 4.71 (2H, s), 2.73 (3H, s). volatiles were removed in vacuo The residue was dissolved in dichloromethane (100 mL) washed with saturated NaHCO3 solution (75 mL), water (75 mL) dried over Na2SO4 The product was purified by flash column chromatography elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (7:1)

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

Procedure: A 1M HCl/EtOH solution (50 mL) was added dropwise to the solution of formaldehyde O-benzyl-oxime (3.85 g, 28.48 mmol) in EtOH at 0° C. The mixture was stirred at room temperature for 1 hour, volatiles were removed in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated NaHCO3 solution (75 mL), water (75 mL), and dried over Na2SO4. The product was purified by flash column chromatography using gradient elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (7:1) to yield O-benzyl-N-methyl-hydroxylamine (1.72 g, 44%). 200 MHz 1H NMR (CDCl3, ppm) 7.40-7.27 (5H, m), 5.53 (1H, br s), 4.71 (2H, s), 2.73 (3H, s). volatiles were removed in vacuo The residue was dissolved in dichloromethane (100 mL) washed with saturated NaHCO3 solution (75 mL), water (75 mL) dried over Na2SO4 The product was purified by flash column chromatography elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (7:1)

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

Procedure: A NaOH (1.25 g, 31.32 mmol) solution in water (6 mL) was added to the mixture of O-benzyl-hydroxylamine hydrochloride (5.00 g, 31.32 mmol) and formaldehyde (˜37 wt. % in H2O) (2.3 mL, 31.32 mmol) in toluene (40 mL). The reaction mixture was stirred at room temperature for 1 h. After this time, the organic phase was separated and the water phase was extracted with dichloromethane (3×30 mL). The combined organic phases were dried over Na2SO4, and concentrated in vacuo to yield formaldehyde O-benzyl-oxime (LI, 4.15 g, 98%). 400 MHz 1H NMR (CDCl3, ppm) 7.40-7.29 (5H, m), 7.09 (1H, d, J=8.2 Hz), 6.47 (1H, d, J=8.2 Hz), 5.14 (2H, s). After this time, the organic phase was separated the water phase was extracted with dichloromethane (3×30 mL) The combined organic phases were dried over Na2SO4 concentrated in vacuo

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

Procedure: 37% Formaldehyde (11.7 mL) was added to a slurry of benzyloxyamine hydrochloride (25.0 g, 0.156 mole) in 50 mL H2O. NaOH (6.3 g) in 25 mL H2O was then added over 20 minutes. The temperature rose to 40°. After stirring 2 hours, the reaction mixture was extracted 1×100 mL and 2×25 mL of ether. The ether extracts were combined, washed 2×50 mL saturated NaHCO3 and then 2×50 mL brine, dried and evaporated to yield title product as an oil, 20.0 g, b.p. 195.5°. rose to 40° the reaction mixture was extracted 1×100 mL and 2×25 mL of ether washed 2×50 mL saturated NaHCO3 2×50 mL brine, dried evaporated

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

Procedure: Lithium hexamethyldisilazane (180 mL, 0.18 mol, 1 M in tetrahydrofuran) under nitrogen was cooled to not more than 5° C. with a ice bath. A solution of 1-benzyl-piperidine-4-carboxylic acid ethyl ester from Example 7B (40.0 g, 0.16 mol) in tetrahydrofuran (450 mL) was added at such a rate as to keep the internal temperature at not more than 5° C., and the mixture was stirred at not more than 5° C. for 1 hour. A solution of formaldehyde O-benzyl-oxime from Example 7A (20.0 g, 0.15 mol) in tetrahydrofuran (200 mL) was added, and the reaction mixture stirred at not more than 5° C. for 1 hour. A saturated aqueous solution of NH4Cl (300 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (300 g) eluting with hexane/ethyl acetate (4:1 to 1:1) to afford the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.54-1.63 (m, 2 H) 1.91 (ddd, J=13.17, 9.47, 3.70 Hz, 2 H) 2.03-2.17 (m, 2 H) 2.68-2.77 (m, 2 H) 3.03 (s, 2 H) 3.45 (s, 2 H) 4.93 (s, 2 H) 7.19-7.42 (m, 10 H). at not more than 5° C. the reaction mixture stirred at not more than 5° C. for 1 hour the layers were separated The aqueous layer was extracted with ethyl acetate (500 mL) The combined organic layers were washed with brine (300 mL) dried over Na2SO4 filtered concentrated in vacuo The resulting residue was purified by flash chromatography on silica gel (300 g) eluting with hexane/ethyl acetate (4:1 to 1:1)

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

Procedure: O-Benzyl-hydroxylamine hydrochloride (125.0 g, 0.78 mol) was combined with toluene (400 mL) under nitrogen. The resulting slurry was cooled in an ice bath and formalin (37%, 75 mL) was added. A 50% solution of NaOH (70 mL) was added portionwise maintaining an internal temperature of not more than 35° C. After the addition of NaOH was complete, water (100 mL) was added and the reaction mixture was stirred at ambient temperature for 2.5 hours. The layers were then separated and the aqueous layer was extracted with toluene. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was distilled (65-70° C., 10 torr) to obtain formaldehyde O-benzyl-oxime. 1H NMR (400 MHz, CDCl3) δ ppm 5.12-5.13 (s, 2 H) 6.46 (d, J=8.23 Hz, 1 H) 7.08 (d, J=8.23 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.36 (dd, J=4.19, 0.62 Hz, 4 H). The resulting slurry was cooled in an ice bath maintaining an internal temperature of not more than 35° C The layers were then separated the aqueous layer was extracted with toluene The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo The resulting oil was distilled (65-70° C., 10 torr)

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

Procedure: O-Benzyl-hydroxylamine hydrochloride (125.0 g, 0.78 mol) was combined with toluene (400 mL) under nitrogen. The resulting slurry was cooled in an ice bath and formalin (37%, 75 mL) was added. A 50% solution of NaOH (70 mL) was added portionwise maintaining an internal temperature of not more than 35° C. After the addition of NaOH was complete, water (100 mL) was added and the reaction mixture was stirred at ambient temperature for 2.5 hours. The layers were then separated and the aqueous layer was extracted with toluene. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was distilled (65-70° C., 10 torr) to obtain formaldehyde O-benzyl-oxime. 1H NMR (400 MHz, CDCl3) δ ppm 5.12-5.13 (s, 2 H) 6.46 (d, J=8.23 Hz, 1 H) 7.08 (d, J=8.23 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.36 (dd, J=4.19, 0.62 Hz, 4 H). The resulting slurry was cooled in an ice bath maintaining an internal temperature of not more than 35° C The layers were then separated the aqueous layer was extracted with toluene The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo The resulting oil was distilled (65-70° C., 10 torr)

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

Procedure: A 1M HCl/EtOH solution (50 mL) was added dropwise to the solution of formaldehyde O-benzyl-oxime (3.85 g, 28.48 mmol) in EtOH at 0° C. The mixture was stirred at room temperature for 1 hour, volatiles were removed in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated NaHCO3 solution (75 mL), water (75 mL), and dried over Na2SO4. The product was purified by flash column chromatography using gradient elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (7:1) to yield O-benzyl-N-methyl-hydroxylamine (1.72 g, 44%). 200 MHz 1H NMR (CDCl3, ppm) 7.40-7.27 (5H, m), 5.53 (1H, br s), 4.71 (2H, s), 2.73 (3H, s). volatiles were removed in vacuo The residue was dissolved in dichloromethane (100 mL) washed with saturated NaHCO3 solution (75 mL), water (75 mL) dried over Na2SO4 The product was purified by flash column chromatography elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (7:1)

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

Procedure: A NaOH (1.25 g, 31.32 mmol) solution in water (6 mL) was added to the mixture of O-benzyl-hydroxylamine hydrochloride (5.00 g, 31.32 mmol) and formaldehyde (˜37 wt. % in H2O) (2.3 mL, 31.32 mmol) in toluene (40 mL). The reaction mixture was stirred at room temperature for 1 h. After this time, the organic phase was separated and the water phase was extracted with dichloromethane (3×30 mL). The combined organic phases were dried over Na2SO4, and concentrated in vacuo to yield formaldehyde O-benzyl-oxime (LI, 4.15 g, 98%). 400 MHz 1H NMR (CDCl3, ppm) 7.40-7.29 (5H, m), 7.09 (1H, d, J=8.2 Hz), 6.47 (1H, d, J=8.2 Hz), 5.14 (2H, s). After this time, the organic phase was separated the water phase was extracted with dichloromethane (3×30 mL) The combined organic phases were dried over Na2SO4 concentrated in vacuo