| 54.5% |
With bromine; In chloroform; at 113℃; for 1.5h;Sealed tube; |
To a stirred solution of piperidine-2,6-dione (30 g, 0.266 mol) in CHCl3 (60 mL) was added Br2 (13.5 mL, 0.265 mol) in a sealed glass tube, then the reaction mixture was heated to 113 C. for 1.5 h. The mixture was cooled to r.t. and transferred to a round bottom flask and concentrated. To the residue was added 100 mL ice water, and the solution was basified to pH=8 with saturated NaHCO3 aqueous, then extracted with DCM (100 mL×5). The organic layer was dried with Na2SO4, filtered, and concentrated to give crude product, which was dissolved in a solution of DCM:EtOAc=1:1 (90 mL), then heated to 80 C. After the solid was completely dissolved, the heating was stopped and the solution was cooled to r.t. for overnight. The solution was filtered, the solid was collected, and dried under vacuum to give desired compound (15.7 g) as a white solid. The filtrate was also concentrated to dry to give crude product, which was purified by column chromatography on silica gel eluting with DCM:Petroleum ether:EtOAc=5:5:1 to DCM:Petroleum ether:EtOAc=5:5:2 to obtain desired the second batch pure product (12 g) as a white solid (total yield: 54.5%). 1H NMR (400 MHz, DMSO-d6) delta 11.06 (s, 1H), 5.00-4.78 (m, 1H), 2.69-2.54 (m, 2H), 2.45 (dd, J=10.0, 5.1 Hz, 1H), 2.17-2.12 (m, 1H). |
| 44% |
With bromine; In 1,1,2-trichloroethane; at 20 - 110℃; for 3h; |
Bromine (9.1 ml, 177 mmol, 1 eq) is added to a solution of glutarimide x54 (20 g, 177 mmol, 1 eq) in 1 ,1 ,2-trichloroethane (60 ml) at room temperature. The mixture is stirred for 2 h at 110 0C, then 1 h at room temperature. The mixture is evaporated to dryness and the residue is purified by chromatography over silicagel (dichloromethane) to afford 14.6 g of 3-bromopiperidine-2, 6-dione x55 as white crystals. Yield: 44 %. LC-MS (MH+): 193. |
| 44.3% |
With bromine; In 1,1,2-trichloroethane; at 20 - 110℃; for 3h; |
Bromine (6.4 g, 0.04 mol) was added to a solution of piperidine-2,6-dione (4.5 g,0.04 mol) in 14 mL of 1 , 1 ,2-trichloroethane at room temperature. The mixture was allowed to stir for 2 hours at 1 10 C and then for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was purified using flash chromatography on silica gel (eluted with PE : EtOAc = 5 : 1 ~ 2 : 1) to provide 3.4 g of 3-bromopiperidine-2,6- dione (yield: 44.3 %) as white solid. 1H-NMR (CDC13, 400 MHz) delta 8.34 (s, 1H), 4.64 (t, / = 3.6 Hz, 1H), 2.91-3.00 (m, 1H), 2.66-2.73 (m, 1H), 2.28-2.47 (m, 2H). |
| 44.3% |
With bromine; In 1,1,2-trichloroethane; at 20 - 110℃; for 3h; |
Bromine (6.4 g, 0.04 mol) was added to a solution of piperidine-2,6-dione (4.5 g,0.04 mol) in 14 mL of 1 , 1 ,2-trichloroethane at room temperature. The mixture was allowed to stir for 2 hours at 1 10 C and then for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was purified using flash chromatography on silica gel (eluted with PE : EtOAc = 5 : 1 ~ 2 : 1) to provide 3.4 g of 3-bromopiperidine-2,6- dione (yield: 44.3 %) as white solid. 1H-NMR (CDC13, 400 MHz) delta 8.34 (s, 1H), 4.64 (t, / = 3.6 Hz, 1H), 2.91-3.00 (m, 1H), 2.66-2.73 (m, 1H), 2.28-2.47 (m, 2H). |
| 44.3% |
With bromine; In 1,1,2-trichloroethane; at 20 - 110℃; for 3h; |
Step 1-Synthesis of 5-bromopyridine-3-carbothioamide Bromine (6.4 g, 0.04 mol) was added to a solution of piperidine-2,6-dione (4.5 g, 0.04 mol) in 14 mL of 1,1,2-trichloroethane at room temperature. The mixture was allowed to stir for 2 hours at 110 C. and then for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was purified using flash chromatography on silica gel (eluted with PE:EtOAc=5:1?2:1) to provide 3.4 g of 3-bromopiperidine-2,6-dione (yield: 44.3%) as white solid. 1H-NMR (CDCl3, 400 MHz) delta 8.34 (s, 1H), 4.64 (t, J=3.6 Hz, 1H), 2.91?3.00 (m, 1H), 2.66?2.73 (m, 1H), 2.28?2.47 (m, 2H). |
| 38% |
With bromine; In chloroform; at 110℃; for 4h;Inert atmosphere; Sealed tube; |
To a stirred solution of piperidine-2,6-dione (5 g, 44.20 mmol) in CHCb (10 mL) was added Br2(2.25 mL) in one portion at room temperature under nitrogen atmosphere. The reaction mixture was sealed in a tube and stirred for 4 hours at 110 C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford 3-bromopiperidine-2,6-dione as a pink solid (3.2 g, 38%): NMR (300 MHz, DMSO-i) delta 11.05 (br s, 1H), 4.89 (dd, J= 5.2, 3.9 Hz, 1H), 2.60 (dt, J= 9.8, 4.7 Hz, 2H), 2.46 (ddd, J= 9.6, 5.1, 3.9 Hz, 1H), 2.15 (dq, J= 14.9, 4.9 Hz, 1H); LC/MS (ESI, m/z): [(M + 1)]+= 192.1, 194. 1. |
| 38% |
With bromine; In chloroform; at 110℃; for 4h;Inert atmosphere; Sealed tube; |
To a stirred solution of piperidine-2,6-dione (5 g, 44.20 mmol) in CHCb (10 mL) was added Br2 (2.25 mL) in one portion at room temperature under nitrogen atmosphere. The reaction mixture was sealed in a tube and stirred for 4 hours at 110 C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford 3-bromopiperidine-2,6-dione as a pink solid (3.2 g, 38%): NMR (300 MHz, DMSO-i) delta 11.05 (br s, 1H), 4.89 (dd, J= 5.2, 3.9 Hz, 1H), 2.60 (dt, J= 9.8, 4.7 Hz, 2H), 2.46 (ddd, J= 9.6, 5.1, 3.9 Hz, 1H), 2.15 (dq, J= 14.9, 4.9 Hz, 1H); LC/MS (ESI, m/z): [(M + 1)]+ = 192.1, 194. 1. |
|
With bromine; In ethanol; chloroform; |
Step 1 3-bromopiperidine-2,6-dione 4.5 ml bromine were added to 10.2 g glutarimide suspended in 20 ml chloroform and the mixture was stirred in a closed vessel for 90 minutes at a bath temperature of 110 C. After cooling, the vessel was opened and stirring was continued until no more hydrogen bromide escaped. The reaction mixture was evaporated in vacuo, the residue dissolved in ethanol and evaporated again. 17.1 g (99% of theoretical) of the title compound remained in the form of practically white crystals, which melted at 76 to 83 C. |
|
With bromine; In chloroform; at 110℃; for 0.75h; |
To a 48mL glass pressure reaction vessel fitted with a Teflon screw cap was added piperidine-2,6-dione (2.00g, 17.7mmol) and Br2 (2.82g, 0.90mL, 17.7mmol) in chloroform (15mL). The reaction mixture was then heated in a Kugelroehr oven at 110C (45min). The solvent was removed and the crude bromoglutarimide 7 was then dissolved in acetone (5mL) followed by the addition of sodium azide (3.44g, 53.1mmol) whereupon the reaction mixture turned blue-purple. The reaction mixture was stirred at room temperature (24h) and then directly applied to a silica gel column. Elution with hexane/ethyl acetate (1:1) gave a mixture of unreacted 3-bromopiperidine-2,6-dione 7 and 3-azidopiperidine-2,6-dione 8 (1:1). The mixture of azide 8 and unreacted bromide 7 was again dissolved in acetone (5mL) and sodium azide (1.15g, 17.7mmol) was added and stirring of the blue-purple reaction mixture was continued at room temperature (24h). Column chromatography (hexane/ethyl acetate, 1:1) of the reaction mixture gave pure 3-azidopiperidine-2,6-dione 9 as an off-white amorphous solid (1.44g, 53% from glutarimide): mp 144-145C; Rf 0.24 (TLC stains blue with heat); 1H NMR (400MHz, CDCl3) delta 4.21 (dd, J=9.6Hz, 8.4Hz, 1H), 2.78 (dt, J=18.4Hz, 5.6Hz, 1H) 2.63-2.54 (m, 1H), 2.23-2.16 (m, 1H), 2.04-1.95 (m, 1H). 13C NMR (400MHz, CDCl3) delta 170.7, 169.2, 58.2, 29.1, 24.0. FTIR (neat) 3090, 2112, 1710, 1676cm-1; HRMS (ESI-TOF) m/z [M+H]+ calcd for C5H6N4O2: 155.0491, Found: 155.0569. |
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