tert-butyl 2-ethylpiperidine-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-Boc-2-ethylpiperidine (1.5 g, 7.0 mmol) in 28 mL of ether was cooled to −60° C. and treated with TMEDA (1.6 mL, 10.85 mmol), followed by sec-BuLi (8.5 mL, 10.85 mmol) dropwise. The mixture was slowly warmed to −20° C., stirred for 30 min, and then cooled to −78° C. The mixture was treated with a solution of dimethyl sulfate (1.6 mL, 16.69 mmol) in ether and slowly warmed to room temperature. The mixture was diluted with water and then extracted with ether. The combined extracts were dried over K2CO3 and concentrated to give a crude product as an oil which was chromatographed on silica with 5% EtOAc/hexane to give 0.88 g (59%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ3.91-3.87 (m, 1 H), 3.69-3.65 (m, 1 H), 1.83-1.41 (m, 17 H), 1.21-1.19 (d, 3 H), 0.85-0.82 (t, 3 H); 13C NMR (62.7 MHz) 155.2 (s), 78.6 (s), 53.0 (s), 46.8 (s), 28.5 (s), 27.2 (s), 26.7 (s), 22.4 (s), 20.7 (s), 13.4 (s), 11.4 (s) ppm. cooled to −78° C slowly warmed to room temperature extracted with ether The combined extracts were dried over K2CO3 concentrated to give a crude product as an oil which was chromatographed on silica with 5% EtOAc/hexane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Under a argon atmosphere a vacuum dried 750 mL four necked flask (with mechanical stirrer) was charged with 6.6 mL diisopropylamine and 100 mL THF. The solution was cooled to −5° C./−10° C. 29.1 mL of 1.6M n-butyllithium in hexane was added over a period of 20 min. The light yellow solution was stirred for 30 min at −5°/−10° C. and afterwards cooled to −75° C. A solution of 10 g (38.8 mmol) ethyl 1-tert-butoxycarbonylpiperidine in 75 mL THF was added over a period of 50 min. The yellow solution was stirred at −75° C. for 2 h. A solution of 9.8 g (46.7 mmol) 2,2,2-trifluoroethyl iodide in 25 mL THF was added dropwise over a period of 45 min. The reaction was stirred for 1 h at −75° C. and allowed to warm up over night to ambient temperature. The reaction was cooled down to 0° C., quenched with 250 mL 10% citric acid aq. solution The aqueous layer was separated and extracted twice with 200 mL ethyl acetate. The organic layers were washed once with 200 mL brine, dried over Na2SO4, filtered and evaporated. Under a argon atmosphere a vacuum dried 750 mL four necked flask (with mechanical stirrer) was charged with 6.6 mL diisopropylamine and 100 mL THF 29.1 mL of 1.6M n-butyllithium in hexane was added over a period of 20 min afterwards cooled to −75° C The yellow solution was stirred at −75° C. for 2 h The reaction was stirred for 1 h at −75° C. to warm up over night to ambient temperature The reaction was cooled down to 0° C. quenched with 250 mL 10% citric acid aq. solution The aqueous layer was separated extracted twice with 200 mL ethyl acetate The organic layers were washed once with 200 mL brine dried over Na2SO4 filtered evaporated

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-Boc-2-ethylpiperidine (1.5 g, 7.0 mmol) in 28 mL of ether was cooled to −60° C. and treated with TMEDA (1.6 mL, 10.85 mmol), followed by sec-BuLi (8.5 mL, 10.85 mmol) dropwise. The mixture was slowly warmed to −20° C., stirred for 30 min, and then cooled to −78° C. The mixture was treated with a solution of dimethyl sulfate (1.6 mL, 16.69 mmol) in ether and slowly warmed to room temperature. The mixture was diluted with water and then extracted with ether. The combined extracts were dried over K2CO3 and concentrated to give a crude product as an oil which was chromatographed on silica with 5% EtOAc/hexane to give 0.88 g (59%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 3.91-3.87 (m, 1H), 3.69-3.65 (m, 1H), 1.83-1.41 (m, 17H), 1.21-1.19 (d, 3H), 0.85-0.82 (t, 3H); 13C NMR (62.7 MHz) 155.2 (s), 78.6 (s), 53.0 (s), 46.8 (s), 28.5 (s), 27.2 (s), 26.7 (s), 22.4 (s), 20.7 (s), 13.4 (s), 11.4 (s) ppm. cooled to −78° C slowly warmed to room temperature extracted with ether The combined extracts were dried over K2CO3 concentrated to give a crude product as an oil which was chromatographed on silica with 5% EtOAc/hexane

Conditions: temp:-35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add N,N,N′,N′-tetrametlhylethylenediamine (1.4 mL, 9.11 mmol), then sec-butyllithium (1.4 M in cyclohexane, 7.2 mL, 10.1 mmol) to 2-ethylpiperidine-1-carboxylic acid tert-butyl ester in diethyl ether (18 mL) at −78° C. under a nitrogen atmosphere. Warm to −35° C. and stir for 1 h. Cool to −78° C. and add (2S)-2-(dibenzylamino)-3-phenylpropanal (3.0 g, 9.11 mmol) in diethyl ether (4 mL) and stir for 30 min. Quench at −78° C. with water, warm to room temperature and extract with diethyl ether. Combine the organic layers, dry (magnesium sulfate) and concentrate. Separate the two major diastereomers of 2-((2S)-2-dibenzylaniino-1-hydroxy-3-phenylpropyl)-6-ethylpiperidine-1-carboxylic acid tert-butyl ester using normal-phase preparative HPLC (Kromasil Si 60, 10 μm, 80×180 mm; 98:2 Hexane:Acetone; 130 mL/min). Add N,N,N′,N′-tetrametlhylethylenediamine (1.4 mL, 9.11 mmol) at −78° C. Cool to −78° C. stir for 30 min Quench at −78° C. with water warm to room temperature extract with diethyl ether dry (magnesium sulfate) concentrate Separate the two major diastereomers of 2-((2S)-2-dibenzylaniino-1-hydroxy-3-phenylpropyl)-6-ethylpiperidine-1-carboxylic acid tert-butyl ester using normal-phase preparative HPLC (Kromasil Si 60, 10 μm, 80×180 mm; 98:2 Hexane:Acetone; 130 mL/min)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-Boc-2-ethylpiperidine (1.5 g, 7.0 mmol) in 28 mL of ether was cooled to −60° C. and treated with TMEDA (1.6 mL, 10.85 mmol), followed by sec-BuLi (8.5 mL, 10.85 mmol) dropwise. The mixture was slowly warmed to −20° C., stirred for 30 min, and then cooled to −78° C. The mixture was treated with a solution of dimethyl sulfate (1.6 mL, 16.69 mmol) in ether and slowly warmed to room temperature. The mixture was diluted with water and then extracted with ether. The combined extracts were dried over K2CO3 and concentrated to give a crude product as an oil which was chromatographed on silica with 5% EtOAc/hexane to give 0.88 g (59%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ3.91-3.87 (m, 1 H), 3.69-3.65 (m, 1 H), 1.83-1.41 (m, 17 H), 1.21-1.19 (d, 3 H), 0.85-0.82 (t, 3 H); 13C NMR (62.7 MHz) 155.2 (s), 78.6 (s), 53.0 (s), 46.8 (s), 28.5 (s), 27.2 (s), 26.7 (s), 22.4 (s), 20.7 (s), 13.4 (s), 11.4 (s) ppm. cooled to −78° C slowly warmed to room temperature extracted with ether The combined extracts were dried over K2CO3 concentrated to give a crude product as an oil which was chromatographed on silica with 5% EtOAc/hexane

Conditions: temp:0.00; pressure:0.00; stir: