1-Methyl-4-piperidone → 5-(4-Hydroxy-1-methyl-piperidin-4-yl)-1,3-dihydroisoindole-2-carboxylic acid tert-butyl ester

HRID 424097Notes

Reaction equation

HRID 424097 reaction equation
C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:27]3([OH:30])[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]

Participants

5

Reactant 3

HCID 740491-Methyl-4-piperidoneHCID 16102683N-Boc-5-bromoisoindolineHCID 178418339Butyllithium

Product 1

HCID 666723445-(4-Hydroxy-1-methyl-piperidin-4-yl)-1,3-dihydroisoindole-2-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

0.69 ml of n-Butyl lithium (2.5M solution in hexane) was added dropwise to a stirred solution of 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (429 mg; 1.44 mmol) in anhydrous THF (10 ml) at −78° C. under an atmosphere of nitrogen. The reaction was stirred for 50 minutes then 1-methyl-4-piperidone (212 μl; 1.2 equiv.) was added and stirred at −78° C. for a further 60 minutes then warmed to room temperature. The reaction was quenched with saturated ammonium chloride solution then extracted with EtOAc. The EtOAc layer was washed with saturated NaHCO3, brine, dried (MgSO4) and evaporated. Purification by flash column chromatography on SiO2, gradient elution from 0% to 10% 2M methanolic ammonia/DCM gave 111 mg of 5-(4-hydroxy-1-methyl-piperidin-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a colourless oil.

Workup

  1. stirringstirred at −78° C. for a further 60 minutes
  2. customThe reaction was quenched with saturated ammonium chloride solution
  3. extractionthen extracted with EtOAc
  4. washThe EtOAc layer was washed with saturated NaHCO3, brine
  5. dry with materialdried (MgSO4)
  6. customevaporated
  7. customPurification by flash column chromatography
  8. washon SiO2, gradient elution from 0% to 10% 2M methanolic ammonia/DCM

Sources & evidence

ORD record
ord-f65addd4430d4cac8aedd066a074a28c
Source dataset
uspto-grants-2012_01
Patent number
US08101648B2

Reaction notes

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