2,2,6,6-Tetramethylpiperidine → HCID 18398757, compound

HRID 1018920Notes

Reaction equation

HRID 1018920 reaction equation
CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][CH:33]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:34])=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[Br:41]C(F)(F)C(F)(F)Br>O1CCCC1>[Br:41][C:24]1[N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])[C:31]2[C:26]([C:25]=1[CH2:32][CH:33]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[CH3:34])=[CH:27][CH:28]=[CH:29][CH:30]=2

Participants

6

Reactant 4

HCID 130352,2,6,6-TetramethylpiperidineHCID 313011,2-Dibromo-1,1,2,2-tetrafluoroethaneHCID 18398765HCID 18398765, compoundHCID 178418339Butyllithium

Product 1

HCID 18398757HCID 18398757, compoundYield 34%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 2,2,6,6-tetramethylpiperidine (5.3 ml, 31.6 mmol) in anhydrous tetrahydrofuran (50 ml) cooled to −78° C. under an atmosphere of nitrogen was added in a dropwise manner n-butyllithium (12.6 ml of a 2.5M solution in hexanes, 31.6mmol). On complete addition the reaction mixture was allowed to warm to 0° C. and stirred at this temperature for 5 minutes. Re-cooled to −78° C. and a solution of the 1-tert-butoxycarbonyl-3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole in anhydrous tetrahydrofuran (50 ml) added via a cannula at such a rate that the temperature did not rise above −50° C. On complete addition the reaction mixture was stirred at −78° C. for 4 hours then 1,2-dibromotetrafluoroethane (3.78 ml, 31.6 mmol) added; the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed in vacuo and the residue purified by column chromatography on silica eluting with 2% CH3OH in CH2Cl2+0.5% 0.88 ammonia to give the title compound (1.5 g, 34%); δH (360 MHz; CDCl3) 1.32 (3H, d, J 6.7 Hz, CH3), 1.71 (9H, s, O2C(CH3)3), 2.99-3.05 (1H, m, indole CHAHB), 3.55-3.67 (1H, m, indole CHAHBCH), 3.74 (1H, d, J 13.2 Hz, indole CHAHB), 7.26-7.33 (2H, m, indole H5+H6), 7.92 (1H, dd, J 6.6 and 3.7 Hz, indole H4), 8.05 (1H, d, J 5.8 and 2.2 Hz, indole H7), piperidine protons very broad and merged into baseline; m/z (ES+) 421/423 (M++H, 100%).

Workup

  1. additionOn complete addition the reaction mixture
  2. customdid not rise above −50° C
  3. additionOn complete addition the reaction mixture
  4. stirringwas stirred at −78° C. for 4 hours
  5. temperatureto warm to room temperature
  6. stirringstirred for 18 hours
  7. customThe solvent was removed in vacuo
  8. customthe residue purified by column chromatography on silica eluting with 2% CH3OH in CH2Cl2+0.5% 0.88 ammonia

Sources & evidence

ORD record
ord-ce0ee37514444a4bae429d090b4cd27d
Source dataset
uspto-grants-2002_11
Patent number
US06486153B1

Reaction notes

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