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Stage #1: With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 40 h; Stage #2: With 10 wt% Pd(OH)2 on carbon; hydrogen In ethanol for 24 h; Stage #3: With hydrogenchloride In 1,4-dioxane; ethanol at 0℃;
A solution of the sub-title product of step (iii) (14.1 g) dissolved in ethanol (100 mL) was treated with 10percent Pd/C (JM type 87L) (1.48 g) under hydrogen. The resulting mixture was stirred at 20 °C for 40 hours at 4.50 bar pressure of hydrogen gas. The Cbz protecting group still attached so switched to palladium hydroxide on carbon (2 g) in ethanol (100 mL). The mixture was hydrogenated for a further 24 hours at 4.50 bar. The mixture was filtered through a pad of celite and filtrate cooled to 0 °C in an ice batch. 4M HCl in dioxane (26.0 mL) was added dropwise and the solution evaporated to dryness to give the title product (7.46 g) as a light brown oil. 1H NMR (400 MHz, CDCL3) δ 9.24 (s, 2H), 3.95 (ddd, J = 7.4, 9.8, 11.4 Hz, 2H), 3.55 - 3.45 (m, 2H), 2.85 (dt, J = 6.7, 14.2 Hz, 1H), 1.16 (d, 3H).
A suspension of methyltriphenylphosphonium bromide (23.0 g, 0.0649 mol) and potassium tert-bvlambdaoxie (7.3 g, 0.0649 mol) in diethyl ether (140 mL) was stirred at room temperature for 20 min, and then heated to 35 0C for 1 h. To this bright yellow reaction EPO <DP n="167"/>mixture was slowly added a dilute solution of phenylmethyl 3-oxoazetidine-l-carboxylate (3.33 g, 0.0162 mol) in diethyl ether (50 mL). The reaction mixture was stirred at 35 0C for 12 hours then filtered through a bed of celite and rinsed with ethyl ether. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 5-10% ethyl acetate in hexanes) to afford phenylmethyl 3-methylideneazetidine-l-carboxylate (2.46 g, 75% yield) as a clear and colorless oil). 1H NMR (400 MHz5 CDCl3): 7.27-7.22 (m, 5H), 5.02 (s, 2H), 4.93-4.90 (m, 2H), 4.48-4.47 (m, 4H). MS (EI) for C12H13NO2: 203 (M+).
With 3-chloro-benzenecarboperoxoic acid In chloroform at 0 - 20℃; for 12h;
3
To a solution of phenylmethyl 3-methylideneazetidine-l-carboxylate (2.46 g, 0.0121 mol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (12.5 g, 0.0726 mol) at 0 0C. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours then quenched with 1 M sodium thiosulfate / saturated aqueous sodium bicarbonate (1 :1). The layers were separated and the organic layer was dried over anhydrous magnesium sulfate then concentrated. The residue was purified by flash chromatography (5- 15% ethyl acetate in hexanes) to afford phenylmethyl l-oxa-5-azaspiro[2.3]hexane-5- carboxylate (2.2 g, 83% yield) as clear and colorless oil. 1H NMR (400 MHz, CDCl3): 7.37- 7.29 (m, 5H), 5.12 (s, 2H), 4.35-4.26 (m, 4H), 2.85 (s, 2H). MS (EI) for C12Hi3NO3: 220 (MH+).
83%
With m-chloroperoxybenzoic acid In chloroform at 0 - 20℃; for 12h;
3
To a solution of phenylmethyl 3-methylideneazetidine-l-carboxylate (2.46 g, 0.0121 mol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (12.5 g, 0.0726 mol) at 0 0C. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours then quenched with 1 M sodium thiosulfate / saturated aqueous sodium bicarbonate (1 :1). The layers were separated and the organic layer was dried over anhydrous magnesium sulfate then concentrated. The residue was purified by flash chromatography (5-15% ethyl acetate in hexanes) to afford phenylmethyl l-oxa-5-azaspiro[2.3]hexane-5-carboxylate (2.2 g, 83% yield) as clear and colorless oil. 1H NMR (400 MHz, CDCl3): 7.37-7.29 (m, 5H), 5.12 (s, 2H)5 4.35-4.26 (m, 4H), 2.85 (s, 2H). MS (EI) for C12Hi3NO3: 220 (MH+).
83%
With 3-chloro-benzenecarboperoxoic acid In chloroform at 0 - 20℃; for 12h;
3
To a solution of phenylmethyl 3-methylideneazetidine-l-carboxylate (2.46 g, 0.0121 mol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (12.5 g, 0.0726 mol) at 0 0C. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours then quenched with 1 M sodium thiosulfate / saturated aqueous sodium bicarbonate (1 : 1). The layers were separated and the organic layer was dried over anhydrous magnesium sulfate then concentrated. The residue was purified by flash chromatography (5- 15% ethyl acetate in hexanes) to afford phenylmethyl l-oxa-5-azaspiro[2.3]hexane-5- carboxylate (2.2 g, 83% yield) as clear and colorless oil. 1H NMR (400 MHz, CDCl3): 7.37- 7.29 (m, 5H), 5.12 (s, 2H), 4.35-4.26 (m, 4H), 2.85 (s, 2H). MS (EI) for C12H13NO3: 220 (MH+).
A suspension of methyltriphenylphosphonium bromide (23.0 g, 0.0649 mol) and potassium tert-butoxide (7.3 g, 0.0649 mol) in diethyl ether (140 mL) was stirred at room temperature for 20 min, and then heated to 35 0C for 1 h. To this bright yellow reaction mixture was slowly added a dilute solution of phenylmethyl 3- oxoazetidine-1-carboxylate (3.33 g, 0.0162 mol) in diethyl ether (50 mL). The reaction mixture was stirred at 35 0C for 12 hours then filtered through a bed of celite and rinsed with ethyl ether. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 5-10% ethyl acetate in hexanes) to afford phenylmethyl 3-methylideneazetidine-l-carboxylate (2.46 g, 75% yield) as a clear and colorless oil). 1H NMR (400 MHz, CDCl3): 7.27-7.22 (m, 5H), 5.02 (s, 2H), 4.93-4.90 (m, 2H), 4.48-4.47 (m, 4H). MS (EI) for Ci2H)3NO2: 203 (M+).
75%
A suspension of methyltriphenylphosphonium bromide (23.0 g, 0.0649 mol) and potassium tert-butoxide (7.3 g, 0.0649 mol) in diethyl ether (140 mL) was stirred at room temperature for 20 min, and then heated to 35 0C for 1 h. To this bright yellow reaction mixture was slowly added a dilute solution of phenylmethyl 3-oxoazetidine-l-carboxylate <n="181"/>(3.33 g, 0.0162 mol) in diethyl ether (50 mL). The reaction mixture was stirred at 35 0C for 12 hours then filtered through a bed of celite and rinsed with ethyl ether. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 5-10% ethyl acetate in hexanes) to afford phenylmethyl 3-methylideneazetidine-l-carboxylate (2.46 g, 75% yield) as a clear and colorless oil). 1H NMR (400 MHz, CDCl3): 7.27-7.22 (m, 5H), 5.02 (s, 2H), 4.93-4.90 (m, 2H), 4.48-4.47 (m, 4H). MS (EI) for C12H13NO2: 203 (M+).
14.1 g
A suspension of methyltriphenylphosphonium bromide (93 g) and potassium tert- butoxide (29.3 g) in diethyl ether (700 mL) was stirred at RT for 20 minutes and heated at 35 C for 1 hour under nitrogen. The bright yellow mixture was treated with the sub-title product of step (ii) (17.9 g) in diethyl ether (200 mL) dropwise over 1 hour at 35 C (orange suspension formed). The resulting mixture was stirred at 35 C for 12 hours. The mixture was cooled and filtered through a pad of celite and washed with diethyl ether. The filtrate was washed with water (300 mL), dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 10%> ethyl acetate in isohexane to 50% ethyl acetate in isohexane (stained with KMn04). Pure fractions were evaporated to dryness to afford the sub -title product (14.1) as a colorless oil.1H NMR (400 MHz, CDCL3) delta 7.39 - 7.28 (m, 5H), 5.12 (s, 2H), 5.01 (m, 2H), 4.57(t, 4H).
14.1 g
A suspension of methyltriphenylphosphonium bromide (93 g) and potassium tert-butoxide (29.3 g) in diethyl ether (700 mL) was stirred at RT for 20 minutes and heated at 35 C for 1 hour under nitrogen. The bright yellow mixture was treated with the sub-title product of step (ii) (17.9 g) in diethyl ether (200 mL) dropwise over 1 hour at 35 C (orange suspension formed). The resulting mixture was stirred at 35 C for 12 hours. The mixture was cooled and filtered through a pad of celite and washed with diethyl ether. The filtrate was washed with water (300 mL), dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 10% ethyl acetate in isohexane to 50% ethyl acetate in isohexane (stained with KMn04). Pure fractions were evaporated to dryness to afford the sub -title product (14.1) as a colorless oil. 1H NMR (400 MHz, CDCL3) delta 7.39 - 7.28 (m, 5H), 5.12 (s, 2H), 5.01 (m, 2H), 4.57 (t, 4H).
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