tert-butyl (2R)-2-formylpiperidine-1-carboxylate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaHMDS (1.0 M in THF, 18.6 mL, 18.6 mmol) was slowly added over 15 min to a 0° C. solution of methyltriphenylphosphonium bromide (7.19 gm, 20.1 mmol) in THF (65 mL). The yellow mixture was stirred at 0° C. for 45 min and then cooled to −78° C. A solution of (R)-tert-butyl 2-formylpiperidine-1-carboxylate (3.30 gm, 15.5 mmol) in THF (10 mL) was added dropwise. The reaction mixture was then stirred at 0° C. for 1 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl. The solution was partitioned between EtOAc and water. The aqueous phase was isolated and extracted with EtOAc. All organic phases were combined, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (R)-tert-butyl 2-vinylpiperidine-1-carboxylate (2.53 gm, 12.0 mmol, 77% yield) as an orange oil. Anal. Calcd. for C12H21N0 m/z 211.3. found: 212.0 (M+H)+. cooled to −78° C The reaction mixture was then stirred at 0° C. for 1 hr The reaction was quenched by the addition of saturated aqueous NH4Cl The solution was partitioned between EtOAc and water The aqueous phase was isolated extracted with EtOAc dried over MgSO4 filtered concentrated The crude product was purified eluting with a gradient of 0-100% EtOAc/Hex

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaHMDS (1.0 M in THF, 18.6 mL, 18.6 mmol) was slowly added over 15 min to a 0° C. solution of methyltriphenylphosphonium bromide (7.19 gm, 20.1 mmol) in THF (65 mL). The yellow mixture was stirred at 0° C. for 45 min and then cooled to −78° C. A solution of (R)-tert-butyl 2-formylpiperidine-1-carboxylate (3.30 gm, 15.5 mmol) in THF (10 mL) was added dropwise. The reaction mixture was then stirred at 0° C. for 1 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl. The solution was partitioned between EtOAc and water. The aqueous phase was isolated and extracted with EtOAc. All organic phases were combined, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (R)-tert-butyl 2-vinylpiperidine-1-carboxylate (2.53 gm, 12.0 mmol, 77% yield) as an orange oil. Anal. Calcd. for C12H21N0 m/z 211.3. found: 212.0 (M+H)+. cooled to −78° C The reaction mixture was then stirred at 0° C. for 1 hr The reaction was quenched by the addition of saturated aqueous NH4Cl The solution was partitioned between EtOAc and water The aqueous phase was isolated extracted with EtOAc dried over MgSO4 filtered concentrated The crude product was purified eluting with a gradient of 0-100% EtOAc/Hex

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

Procedure: LiAlH4 (110 mg, 2.89 mmol) was added in portions to a 0° C. solution of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (525 mg, 1.93 mmol) in ether (9 mL). The reaction mixture was then stirred at rt for 30 min. The reaction mixture was cooled to 0° C. and carefully quenched by dropwise addition of aqueous 5% KHSO4 (10 mL). The mixture was then extracted with ether (2×15 mL). The organic extracts were combined, washed with 10% aqueous citric acid, 5% aqueous NaHCO3 and saturated aqueous NaCl. The ether was then dried over MgSO4, filtered and concentrated to give (R)-tert-butyl 2-formylpiperidine-1-carboxylate (392 mg, 1.84 mmol, 95% yield) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.59 (1H, s), 4.71-4.44 (1H, m), 4.12-3.79 (1H, m), 3.05-2.78 (1H, m), 2.17 (1H, d, J=11.5 Hz), 1.73-1.55 (4H, m), 1.46 (9H, s), 1.34-1.18 (1H, m). The reaction mixture was cooled to 0° C. carefully quenched by dropwise addition of aqueous 5% KHSO4 (10 mL) The mixture was then extracted with ether (2×15 mL) washed with 10% aqueous citric acid, 5% aqueous NaHCO3 and saturated aqueous NaCl The ether was then dried over MgSO4 filtered concentrated

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

Procedure: To the title compound of Example 2.1 (3.0 g, 14.1 mmol) in MeOH/H2O (30 mL/30 mL) in an ice-bath was added Na2CO3 (895 mg, 8.4 mmol) and hydroxylamine hydrochloride (1.2 g, 16.9 mmol). After stirring for 30 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated to half volume and then extracted with ethyl acetate (2 times), washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil (3.1 g, 97%). stirred for an additional 4 hours The reaction mixture was concentrated to half volume extracted with ethyl acetate (2 times) washed with saturated brine dried over anhydrous Na2SO4 filtered concentrated

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

Procedure: To the title compound of Example 2.1 (3.0 g, 14.1 mmol) in MeOH/H2O (30 mL/30 mL) in an ice-bath was added Na2CO3 (895 mg, 8.4 mmol) and hydroxylamine hydrochloride (1.2 g, 16.9 mmol). After stirring for 30 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated to half volume and then extracted with ethyl acetate (2 times), washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil (3.1 g, 97%). stirred for an additional 4 hours The reaction mixture was concentrated to half volume extracted with ethyl acetate (2 times) washed with saturated brine dried over anhydrous Na2SO4 filtered concentrated

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

Procedure: To the title compound of Example 1.1 (5.4 g, 22.1 mmol) in toluene (50 mL) at −78° C. was added 1.5 M DIBAL in toluene (33.8 mL, 50.7 mmol) drop-wise over 40 minutes. Methanol (120 mL) was then added drop-wise at −78° C. over 10 minutes. The reaction mixture was moved to an ice-bath where 10% wt citric acid (500 mL) was added and then mixture was stirred for an additional 1 hour. After the resulting mixture was extracted with ethyl acetate (2 times), the organic layer washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil (3.0 g, 64%). The reaction mixture was moved to an ice-bath After the resulting mixture was extracted with ethyl acetate (2 times) the organic layer washed with water and brine dried over anhydrous Na2SO4 filtered concentrated

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

Procedure: To the title compound of Example 1.1 (5.4 g, 22.1 mmol) in toluene (50 mL) at −78° C. was added 1.5 M DIBAL in toluene (33.8 mL, 50.7 mmol) drop-wise over 40 minutes. Methanol (120 mL) was then added drop-wise at −78° C. over 10 minutes. The reaction mixture was moved to an ice-bath where 10% wt citric acid (500 mL) was added and then mixture was stirred for an additional 1 hour. After the resulting mixture was extracted with ethyl acetate (2 times), the organic layer washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil (3.0 g, 64%). The reaction mixture was moved to an ice-bath After the resulting mixture was extracted with ethyl acetate (2 times) the organic layer washed with water and brine dried over anhydrous Na2SO4 filtered concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaHMDS (1.0 M in THF, 18.6 mL, 18.6 mmol) was slowly added over 15 min to a 0° C. solution of methyltriphenylphosphonium bromide (7.19 gm, 20.1 mmol) in THF (65 mL). The yellow mixture was stirred at 0° C. for 45 min and then cooled to −78° C. A solution of (R)-tert-butyl 2-formylpiperidine-1-carboxylate (3.30 gm, 15.5 mmol) in THF (10 mL) was added dropwise. The reaction mixture was then stirred at 0° C. for 1 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl. The solution was partitioned between EtOAc and water. The aqueous phase was isolated and extracted with EtOAc. All organic phases were combined, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (R)-tert-butyl 2-vinylpiperidine-1-carboxylate (2.53 gm, 12.0 mmol, 77% yield) as an orange oil. Anal. Calcd. for C12H21N0 m/z 211.3. found: 212.0 (M+H)+. cooled to −78° C The reaction mixture was then stirred at 0° C. for 1 hr The reaction was quenched by the addition of saturated aqueous NH4Cl The solution was partitioned between EtOAc and water The aqueous phase was isolated extracted with EtOAc dried over MgSO4 filtered concentrated The crude product was purified eluting with a gradient of 0-100% EtOAc/Hex

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

Procedure: LiAlH4 (110 mg, 2.89 mmol) was added in portions to a 0° C. solution of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (525 mg, 1.93 mmol) in ether (9 mL). The reaction mixture was then stirred at rt for 30 min. The reaction mixture was cooled to 0° C. and carefully quenched by dropwise addition of aqueous 5% KHSO4 (10 mL). The mixture was then extracted with ether (2×15 mL). The organic extracts were combined, washed with 10% aqueous citric acid, 5% aqueous NaHCO3 and saturated aqueous NaCl. The ether was then dried over MgSO4, filtered and concentrated to give (R)-tert-butyl 2-formylpiperidine-1-carboxylate (392 mg, 1.84 mmol, 95% yield) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.59 (1H, s), 4.71-4.44 (1H, m), 4.12-3.79 (1H, m), 3.05-2.78 (1H, m), 2.17 (1H, d, J=11.5 Hz), 1.73-1.55 (4H, m), 1.46 (9H, s), 1.34-1.18 (1H, m). The reaction mixture was cooled to 0° C. carefully quenched by dropwise addition of aqueous 5% KHSO4 (10 mL) The mixture was then extracted with ether (2×15 mL) washed with 10% aqueous citric acid, 5% aqueous NaHCO3 and saturated aqueous NaCl The ether was then dried over MgSO4 filtered concentrated