2,2,6,6-Tetramethylpiperidine → 1-(3-Bromo-2-fluoro-phenyl)-4-dimethylamino-cyclohexanol

HRID 970728Notes

Reaction equation

HRID 970728 reaction equation
[Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[CH3:24][N:25]([CH3:33])[CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>>[Br:16][C:17]1[C:18]([F:23])=[C:19]([C:29]2([OH:32])[CH2:30][CH2:31][CH:26]([N:25]([CH3:33])[CH3:24])[CH2:27][CH2:28]2)[CH:20]=[CH:21][CH:22]=1

Participants

5

Reactant 4

HCID 130352,2,6,6-TetramethylpiperidineHCID 612591-Bromo-2-fluorobenzeneHCID 103745454-(Dimethylamino)cyclohexan-1-oneHCID 178418339Butyllithium

Product 1

HCID 588523751-(3-Bromo-2-fluoro-phenyl)-4-dimethylamino-cyclohexanol

Procedure

Add n-BuLi (20.2 mL, 1.6M in hexanes, 32.3 mmol) into a solution of 2,2,6,6-tetramethyl-piperidine (4.56 g, 32.6 mmol) in hexanes (30 mL) at −78° C. Add 1-bromo-2-fluoro-benzene (4.71 g, 26.9 mmol) and stir for 1 hr. Slowly add 4-dimethylamino-cyclohexanone (3.80 mL) in hexanes (30 mL) and stir for 1 hr. Remove the cooling bath and stir for two more hours. Partition the reaction mixture between saturated aqueous NaCl and ethyl acetate, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by chromatography on a silica gel column (DCM: 2M NH3 in MeOH, gradient) to give the title compound (2.04 g): MS (ES): m/z=318 (M+H)+ and 316 (M−H)−. 1HNMR (CDCl3): δ 7.43 (m, 2H), 6.98 (m, 1H), 2.45 (m, 2H), 2.21 (s, 6H), 2.13 (m, 1H), 1.92 (m, 2H), 1.64 (m, 4H).

Workup

  1. customRemove the cooling bath
  2. customPartition the reaction mixture between saturated aqueous NaCl and ethyl acetate
  3. dry with materialdry the organic phase with anhydrous sodium sulfate
  4. customevaporate the solvent
  5. custompurify the residue by chromatography on a silica gel column (DCM: 2M NH3 in MeOH, gradient)

Sources & evidence

ORD record
ord-26bfe8f58b364ad38dd361c2b1fb1bd4
Source dataset
uspto-grants-2007_12
Patent number
US07312236B2

Reaction notes

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