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A solution of <strong>[199174-24-8](S)-3-hydroxymethylpyrrolidine-1-carboxylic acid t-butyl ester</strong> (25.0 g, 124 mmol) in DCM (200 mL) was cooled with stirring to 0 C. A solution of potassium bromide (1.5 g, 12.4 mmol) and sodium bicarbonate (1.5 g, 17.4 mmol) dissolved in water (100 mL) was added. After 15 minutes of stirring at 0 C. 2,2,6,6,-tetramethylpiperidin-1-oxyl (195.3 mg, 1.2 mmol) was added, followed by the slow addition of sodium hypochlorite (77.3 mL, 136.6 mmol) dropwise keeping the internal temperature in the 6-8 C. range. The mixture was placed in an ice bath until the layers separated and the layers were back extracted with DCM (200 mL). The combined organic layers were washed with 1M NaCl in water (200 mL), dried over Na2SO4, filtered and concentrated to yield crude (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (21.5 g). |
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With 4-methyl-morpholine; oxalyl dichloride; dimethyl sulfoxide; In dichloromethane; at -78 - 0℃; for 1.33333h; |
Step 2: tert-butyl (3S)-3-formylpyrrolidine-1-carboxylateOxalyl chloride (1.4 mL, 16 mmol) was dissolved in DCM (28 mL) and this solution was cooled to -78 C., then DMSO (1.8 mL, 26 mmol) was added. To this was then added a solution of <strong>[199174-24-8]tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate</strong> (2.15 g, 10.7 mmol) in DCM (28 mL), followed in 20 min by addition of 4-methylmorpholine (5.9 mL, 53 mmol). The reaction was held at -78 C. for 20 min, then warmed to 0 C. for 1 h, at which time tlc analysis showed complete oxidation to aldehyde. The reaction was quenched by addition of water and CHCl3, the phases were separated and the aqueous phase was extracted with additional CHCl3. The combined organic phase was washed with water, then 1N HCl, then sat'd NaHCO3, sat'd NaCl, dried over MgSO4 and reduced in vacuo to leave the crude product which was used without further purification, 2.1 g. 1H NMR (300 MHz, CDCl3): delta 9.68 (s, 1H), 3.68 (m, 1H), 3.50 (m, 1H), 3.37 (m, 2H), 3.0 (m, 1H), 2.13 (m, 2H), 1.42 (s, 9H). MS (EI): 144.1 (M-tBu+2H), 126.0 (M-OtBu). |
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With sodium hypochlorite; sodium hydrogencarbonate; potassium bromide;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In dichloromethane; at 0 - 8℃;Product distribution / selectivity; |
Preparation 1(R)-3-vinylpyrrolidine-1-carboxylic Acid t-Butyl Ester ; A solution of <strong>[199174-24-8](S)-3-hydroxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester</strong> (25.0 g, 124 mmol, 1.0 eq.) in DCM (200 mL) was cooled with stirring to 0 C. A solution of potassium bromide (1.5 g, 12.4 mmol, 0.1 eq.) and sodium bicarbonate (1.5 g, 17.4 mmol, 0.14 eq.) dissolved in water (100 mL) was added. After 15 minutes of stirring at 0 C., TEMPO (195.3 mg, 1.2 mmol, 0.01 eq.) was added, followed by the slow addition of sodium hypochlorite (77.3 mL, 1.1 eq.) dropwise keeping the internal temperature in the 6-8 C. range. The mixture was placed in an ice bath until the layers separated. The organic layer was separated and the aqueous layer was extracted with DCM (200 mL). The combined organic layers were washed with saturated aqueous NaCl (200 mL), dried over Na2SO4, filtered, and concentrated to yield crude (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (21.5 g). |
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With sodium hypochlorite; sodium hydrogencarbonate;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide; In dichloromethane; water; at 6 - 8℃;Cooling with ice; |
Preparation 1^ -3-vinylpyrrolidine-l-carboxylic Acid f-Butyl Ester; A solution of (S)-3-hydroxymethyl-pyrrolidine-l-carboxylic acid ?-butyl ester (25.0 g, 124 mmol, 1.0 eq.) in DCM (200 mL) was cooled with stirring to 0C. A solution of potassium bromide (1.5 g, 12.4 mmol, 0.1 eq.) and sodium bicarbonate (1.5 g,17.4 mmol, 0.14 eq.) dissolved in water (100 mL) was added. After 15 minutes of stirring at 0C, TEMPO (195.3 mg, 1.2 mmol, 0.01 eq.) was added, followed by the slow addition of sodium hypochlorite (77.3 mL, 136.6 mmol, 1.1 eq.) dropwise keeping the internal temperature in the 6-8C range. The mixture was placed in an ice bath until the layers separated. The organic layer was separated and the aqueous layer was extracted with DCM (200 mL). The combined organic layers were washed with saturated aqueous NaCl (200 mL), dried over Na2S04, filtered, and concentrated to yield crude compound la (21.5 g). |
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With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide; In dichloromethane; water; at 0℃; for 0.166667h; |
To a solution of <strong>[199174-24-8](S)-3-hydroxymethylpyrrolidine-1-carboxylic acid t-butyl ester</strong> 9 (7.4 g, 37 mmol) in DCM (74 mL, 1.2 mol) was added TEMPO (100 mg, 0.7 mmol) and potassium bromide (200 mg, 2 mmol). This mixture was cooled to 0C and vigorously stirred as a pre-chilled (at 0C) 1:1 mixture of 0.7 M of NaOCl in water (78 mL, 55 mmol) and a saturated, aqueous NaHCO3 solution (75 mL) was added dropwise over a period of 10 minutes. The resultant mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), then saturated aqueous NaCl (1 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield compound 10, which was used without further purification (5.8 g, 80% yield). 1H NMR (400 MHz, CDCl3) delta (ppm) = 9.62 (d, J = 1.6 Hz, 1H), 3.74-3.54 (m, 1H), 3.54-3.38 (m, 1H), 3.38-3.17 (m, 2H), 3.06 - 2.84 (m, 1H), 2.23 - 1.88 (m, 2H), 1.39 (s, 9H). |
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A solution of <strong>[199174-24-8](S)-3-hydroxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester</strong> (25.0 g, 124 mmol, 1.0 eq.) in DCM (200 mL) was cooled with stirring to 0C. A solution of potassium bromide (1.5 g, 12.4 mmol, 0.1 eq.) and sodium bicarbonate (1.5 g,17.4 mmol, 0.14 eq.) dissolved in water (100 mL) was added. After 15 minutes of stirring at 0C, TEMPO (195.3 mg, 1.2 mmol, 0.01 eq.) was added, followed by the slow addition of sodium hypochlorite (77.3 mL, 136.6 mmol, 1.1 eq.) dropwise keeping the internal temperature in the 6-8C range. The mixture was placed in an ice bath until the layers separated. The organic layer was separated and the aqueous layer was extracted with DCM(200 mL). The combined organic layers were washed with saturated aqueous NaC1 (200 mL), dried over Na2504, filtered, and concentrated to yield crude (S)-3- formylpyrrolidine-1-carboxylic acid t-butyl ester (21.5 g). |
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To a solution of oxalyl chloride (22.17 g, 0.176 mol) in CH2Cl2 (200 mL) was added dropwise a solution of DMSO ( 20.59 g, 0.264 mol) in CH2Cl2 (50 mL) at -78 C. The mixture was stirred for 0.5 hrs at this temperature. A solution of (S)-tert-butyl 3- (hydroxymethyl)pyrrolidine-l-carboxylate (M6) (11.8 g, 58.7 mmol) in CH2Cl2 (50 mL) was added dropwise to the reaction mixture at -78 0C. The mixture continued to stir for 1 hr at that temperature. Et3N (29.7 g, 0.294 mol) was added at -78 0C. The resultant mixture was warmed to room temperature and stirred for 3 hrs. The mixture was poured into saturated aqueous NaHCO3 and shaken'. The organic layer was separated, washed twice with water, dried and evaporated to give a residue, which was purified by column chromatography (P.E./EtOAc 5:1) to give (S)-tert-butyl 3-formylpyrrolidine-l-carboxylate (M7). 1H NMR (CDCl3, 300 MHz): delta 9.68 (d, J = 1.8 Hz, 1 H), 3.67-3.68 (m, 1 H), 3.51-3.55 (m, 1 H), 3.35-3.40 (m, 2 H), 2.99-3.04 (m, 1 H), 2.04-2.18 (m, 2 H), 1.46 (s, 9 H). |
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