| 80% |
With potassium hydroxide; iodine at 0 - 5℃; for 1.5h; |
|
| 72% |
With iodine; potassium hydroxide at 0 - 20℃; for 16.75h; |
32
ferf-Butyl 4-oxo-1 -piperidinecarboxylate (2.00 g, 10 mmol) was dissolved in methanol (20 ml.) and cooled to 0 degrees Celsius. Powdered potassium hydroxide (1 .26 g, 22.1 mmol) was added. Iodine (2.8 g, 1 1 mmol) was dissolved in methanol (25 ml.) and was added drop wise to the reaction over 45 minutes. The reaction was then slowly warmed up to room temperature and stirred for 16 hours. The reaction was concentrated and toluene (50 ml.) was added. The resulting solids were filtered off and washed with toluene. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient from 30% to 100% ethyl acetate in heptane to give ferf-butyl 3-hydroxy-4,4-dimethoxypiperidine-1 -carboxylate (1 .89 g, 72%). 1 H NMR (deuteromethanol, 400 MHz) delta ppm 4.06-4.00 (m, 1 H), 3.99-3.91 (m, 1 H), 3.80-3.73 (m, 1 H), 3.29 (s, 3H), 3.28 (s, 3H), 3.22-3.10 (br m, 1 H), 2.95-2.80 (br m, 1 H), 1 .91 -1 .77 (m, 2H), 1 .50 (s, 9 H). |
| 70% |
With potassium hydroxide; iodine at 0 - 20℃; for 2.5h; |
2.A
A. Preparation of tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate The title compound was prepared by taking tert-Butyl 4-Oxo-1-piperidinecarboxylate (2 g, 0.01 mol) in Methanol (19 mL, 0.47 mol) and adding Potassium hydroxide (1.3 g, 0.024 mol;) at 0° C. To this mixture was added Iodine (2.8 g, 0.011 mol) in Methanol (21 mL, 0.52 mol) dropwise over 30 min to keep the internal temperature close to 0° C. The reaction was then allowed to warm to ambient temperature for 2 h. The reaction was then concentrated in vacuo and the residue was dissolved in toluene (20 mL) and filtered. The filtrate was purified via flash chromatography to afford an oil (1.8 g, 70%) which has the same NMR as described in Zacuto, Michael J.; Cai, Dongwei., Tetrahedron Letters, 2005, 46(3), 447-450. 1H NMR (CD3OD, 400 MHz) d 4.06-4.00 (m, 1H), 3.99-3.91 (m, 1H), 3.80-3.73 (m, 1H), 3.29 (s, 3H), 3.28 (s, 3H), 3.22-3.10 (br m, 1H), 2.95-2.80 (br m, 1H), 1.91-1.77 (m, 2H), 1.50 (s, 9 H). |
| 70% |
With iodine; potassium hydroxide at 0 - 20℃; for 2h; |
34.A
To a stirred solution of /ert-butyl-4-oxo-l-piperidinecarboxylate (1.0 g, 5 mmol) in methanol (10 mL), KOH (0.65 g, 12 mmol) was added at 0°C. To this mixture, iodine (1.65 g, 6.52 mmol) in methanol (10 mL) was added drop wise at 0°C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue was purified by flash chromatography to give r/-butyl 3-hydroxy-4,4-dimethoxypiperidine-l-carboxylate as oil (0.917 g, 70%). MS: 284 (M+ 23), 1H NMR (400 MHz, CDC13) δ; 1.45 (s, 9H), 1.70-1.78 (m, 2H), 1.99-2.04 (m, 1H), 2.82-2.85 (m, 1H), 3.10-3.13 (m, 1H), 3.24 (s, 3H), 3.25 (s, 3H), 3.74-3.79 (m, 1H), 3.90- 4.14 (m, 2H). |
| 60% |
With iodine; potassium hydroxide at 0 - 20℃; |
1.1 1) tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate
In a dry 10 L three-mouth flask, add 3800 ml methanol and 311g potassium hydroxide. The reaction cooled to 0 °C, 38 g N-tert-butoxycarbonyl-4-piperidone to the reaction solution. 532 g elemental iodine dissolved in 3000 ml methanol. Slowly add dropwise into the reaction solution. The reaction solution stirring at the room temperature until disappearance of the raw material. Concentrating the reaction solution to remove most of the methanol. Adding 1500 ml toluene to the reaction bottle, and stir for 30 minutes. Filtering to remove the inorganic salt. Reduced pressure distillation to remove the solvent. By adding 400 ml petroleum ether to the reaction bottle, stirring 30 minutes. Obtained after filtering the yellow solid. Decompression drying to obtain 30g product, yield 60%. |
| 59% |
Stage #1: methanol; N-tert-butyloxycarbonylpiperidin-4-one With potassium hydroxide at 0 - 5℃; for 0.25h;
Stage #2: With iodine In methanol at 0 - 20℃; for 7h; |
44A
Potassium hydroxide powder (4.75 g, 72.0 mmol) was dissolved in methanol (60 mL) and cooled to 0-50C. tert-Butyl 4-oxopiperidine-l -carboxylate (5.98 g, 30.0 mmol) was added, and the mixture was stirred for 15 min. A solution of iodine (8.38 g, 33.0 mmol) in methanol (60 mL) was added within 2 h. The reaction mixture was warmed to rt and stirred for further 5 h. The solution was then concentrated in vacuo, and the residue was triturated with toluene and filtered. The solvent was removed in vacuo to yield 5.24 g of a brown oil (88% purity, 59% yield) which was used in the next step without purification.GC/MS (method 1): R, = 5.78 min; MS (DCI): m/z = 262 [M+H]+. |
| 57.9% |
With I,I-bis(acetoxy)iodobenzene; potassium hydroxide at 0 - 5℃; for 12h; |
|
|
With iodine; potassium hydroxide at 0 - 20℃; for 2.5h; |
7.i; 16
To a solution of l,l-dimethylethyl 4-oxo-l-piperidinecarboxylate (lOg, 0.05mol, commercially available from e.g. Sigma-Aldrich, Fluka or Apollo) in MeOH (100ml), was added potassium hydroxide ( 5.2g, 0.09mol), at 0°C. A solution of iodine (14g, 0.055mol) in MeOH (100ml) was added to the above stirred reaction mixture dropwise over 0.5 hours at 0-5°C. The reaction mixture was then allowed to warm up to room temperature and stirred for another 2 hours. After that the resulting solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with Pet Eth EtOAC 10/1 to obtain the desired product D16 as a yellow oil in l lg. |
|
With iodine; potassium hydroxide at 0 - 15℃; for 12h; |
1 Step 1 - (±)-Tert-butyl 3-hydroxy-4,4-dimethoxy-piperidine-1-carboxylate
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (6.00 g, 30.1 mmol) in methanol (40.0 mL) was added potassium hydroxide (3.72 g, 66.3 mmol) and iodine (8.41 g, 33.1 mmol) in several portions at 0 °C. The reaction was warmed to 15 °C and stirred for 12 hrs. On completion, the reaction was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to give tert-butyl 3-hydroxy-4,4- dimethoxy-piperidine-1-carboxylate. LCMS: (ES+) m/z (M+23)+ = 284.2, |
|
With iodine; potassium hydroxide at 0 - 20℃; for 4.5h; |
5.1 Step 1) Tert-Butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate
At 0 °C, potassium hydroxide (6.73 g, 120.0 mmol) in methanol (105 mL)To the solution was added tert-butyl 4-oxopiperidine-1-carboxylate (9.96 g, 50.0 mmol).After stirring the mixture for 10 minutes,A solution of iodine (13.96 g, 55.0 mmol) in methanol (95 mL) was slowly added thereto.Addition time over 1.5 hours.The reaction was stirred at room temperature for 3 hours and then concentrated under reduced pressure.The residue was diluted with toluene (250 mL) and filtered. The filtrate was concentrated under pressure to give the title compound as a yellow oil (13.1 g,100%). The product was used directly for the next reaction without purification. |
|
Stage #1: methanol; N-tert-butyloxycarbonylpiperidin-4-one With potassium hydroxide at 0℃; for 0.333333h;
Stage #2: With [bis(acetoxy)iodo]benzene at 0 - 20℃; |
27
A solution of 21.3 g (380 mmol) KOH in 100 mL dry MeOH was cooled in an ice water bath before 17.6 g (88 mmol) of tert-butyl 4-oxopiperidine-l-carboxylate was added portionwise. The mixture was stirred 20 min before 42.9 g (133 mmol) of iodobenzene diacetate was added portionwise and the mixture was allowed to warm to warm to room temperature with stirring overnight. Solvent was removed, and the residue was partitioned between water and EtOAc. The aqueous layer was saturated with NaCl and the EtOAc was separated. The aqueous layer was extracted 3 times more with EtOAc, and the combined EtOAc layers were dried (MgSO4) and concentrated. Chromatography on silica gel (100% DCM with gradient elution to 100% EtOAc) afforded 21.3 g of product as a white solid. NMR (CDCl3): 1.58 (s, 9 H), 1.73-1.92 (m, 2 H), 2.00 (s, broad, 1 H), 2.91 (m, 1 H), 2.05- 2.34 (m, 2 H), 3.25 (2s, 6 H), 3.75 (m, 1 H), 3.82-4.16 (m, 2 H). |
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