| 90% |
With sodium hydrogencarbonate In dichloromethane; water at 0℃; for 17h; |
|
| 83% |
In neat (no solvent) at 50℃; for 0.0666667h; Microwave irradiation; Green chemistry; chemoselective reaction; |
Typical experimental procedure of N-benzyloxycarbonylation protection on amines derivatives promoted by microwave irradiation
General procedure: Benzylcholoroformate Cbz-Cl (1 mmol) was added to amine (1 mmol) and the mixture was subjected to the microwave irradiation (100W) for the appropriate time (tables 2, 3, 4 and 5). After completion of the reaction (monitored by TLC) dichloromethane: methanol (98/2), the reaction mixture was treating with n-hexane (15-20 mL) and was allowed to stand at room temperature overnight. The solid products were collected by filtration, washed with n-hexane and dried to give the N-Cbz derivatives in good to excellent yields. During the reaction, the formation of hydrogen chloride (gas) was observed, confirming the protection of all amines structures proposal. |
| 82% |
With triethylamine In dichloromethane at 0 - 20℃; |
|
| 72% |
With triethylamine In dichloromethane at 0 - 20℃; |
|
| 45% |
With sodium hydrogencarbonate In dichloromethane; water at 20℃; for 20h; |
|
| 38% |
With sodium hydrogencarbonate In dichloromethane; water Ambient temperature; |
|
|
With sodium hydroxide |
|
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With sodium hydrogencarbonate In dichloromethane for 2h; Ambient temperature; |
|
|
With potassium carbonate In water |
|
|
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃; for 2.16667h; Yield given; |
|
|
With sodium hydrogencarbonate In methanol; water Heating; |
|
|
With triethylamine In hexane; chloroform; ethyl acetate |
1.d d.
d. N-Benzyloxycarbonyl-L-valinol Benzyl chloroformate (91.0 g, 95% purity) was added dropwise over a period of 1 h to a precooled (0° C.) solution of L-valinol (50.0 g) and triethylamine (60.0 g) in chloroform (1500 ml). The reaction mixture was stirred for 1 h at 0° C. and then allowed to warm to,room temperature over 2 h. After the reaction mixture was evaporated, ethyl acetate (1500 ml) was added to the residue and the organic solution was washed (1N NaOH, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, using a stepwise gradient elution of ether:hexane (1:5) followed by ether, to give the alcohol (91.4 g) as a white waxy solid; TLC, Rf =0.23, hexane:ethanol (50:50). |
|
With triethylamine In hexane; chloroform; ethyl acetate |
1.a a.
a. N-Benzyloxycarbonyl-L-valinol Benzyl chloroformate (91.0 g, 95% purity) was added dropwise over a period of 1 hr to a precooled (0°) solution of L-valinol (50.0 g) and triethylamine (60.0 g) in chloroform (1500 ml). The reaction mixture was stirred for 1 hr at 0° and then allowed to warm to room temperature over 2 hr. After the reaction mixture was evaporated, ethyl acetate (1500 ml) was added to the residue: and the organic solution was washed with lN NaOH and brine, dried (MgSO4), and evaporated. The resulting residue purified by flash chromatography, using a stepwise gradient of ether:hexane (1:5) followed by ether, to give the product (91.4 g) as a white waxy solid; TLC, Rf =0.23, hexane:ether (50:50). |
|
With sodium hydrogencarbonate In dichloromethane; water at 0 - 20℃; |
|
|
With potassium carbonate In tetrahydrofuran; water at 0 - 28℃; for 1h; |
|
|
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; |
Synthesis of AE5.
Preparation of l-[(2S)-2-amino-3-methylbutyal]piperidin-2-one (0491) (AE4): A solution of L-valinol (AE1) (4.81 g, 46.6 mmol) in CH2C12 (100 niL) chilled to 0 °C was treated with benzyl chloroformate ((7.3 niL, 51.3 mmol) followed by Hunig's base (16.2 mL, 46.6 mmol). The reaction mixture was allowed to warm up to room temperature and stirred overnight. (0492) The reaction mixture was diluted with ethyl acetate (500 mL), and consecutively washed with 10% (0493) KH2PO4, saturated NaHC03 and brine. The organic layer was dried (anhydrous MgS04) and concentrated in vacuo to provide the protected L-valinol (AE2) (11.14 g, 100%) that was used without further purification. To a solution of AE2 in CH2CI2 (100 mL) at 0 °C was added pyridine (0494) (22.6 mL, 46.6 mmol) and methane sulfonyl chloride. The mixture was allowed to warm up to room temperature and stirred overnight, concentrated, redissolved in EtOAc, and washed with saturated NaHC03 followed by brine. The organic layer was dried (anhydrous MgS04) and concentrated in vacuo and the residue was purified on silica gel eluted with EtOAc/ hexanes to provide mesylate AE3. A solution of AE3 (4.84, 15.34 mmol) in toluene (112 mL) containing water (620 μ) was treated with tetrabutylammoniun bromide (900 mg, 2.80 mmol), K2C03 (4.24 g, 30.7 mmol) and 2-hydroxypyridine (1.45 g, 15.3 mmol). The reaction mixture was heated to reflux with stirring, filtered and the filtrate was concentrated in vacuo. The residue was purified on silica gel eluted with EtOAc/ CH2CI2 (gradient) to yield AE4 (1.65 g, 34%). Compound AE4 in MeOH (50 mL) was treated with Pd/C (10% w/w) (500 mg), placed in a Parr shaker, degassed and back-filled with then hydrogenated at 40 psi for 24 h at room temperature to provide AE5 that was used without further purification. lU NMR (300 MHz, METHANOL-d4) δ 3.55 (dd, = (0495) 9.42, 13.56 Hz, 1H), 3.20-3.31 (m, 2H), 2.89 (td, = 4.54, 9.18 Hz, 1H), 2.38 (t, = 6.03 Hz, 1H), (0496) 2.32 (t, = 6.40 Hz, 1H), 1.72-1.92 (m, 6H), 0.84-1.08 (m, 6H); 13C NMR (75 MHz, (0497) METHANOLS) δ 173.3, 55.5, 52.4, 43.0, 33.1, 32.1, 23.1, 21.8, 19.5, 17.7; MS (ESI) mlz 185.2 (0498) (M + H)+. |
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With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 25℃; for 10h; Inert atmosphere; |
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