2-Bromo-m-xylene → (1-(2,6-Dimethylphenyl)pyrrolidin-3-yl)methanol

HRID 469161Notes

Reaction equation

HRID 469161 reaction equation
Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].Cl.[NH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O.C(=O)(O)[O-].[Na+]>O1CCCC1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12]1

Participants

9

Reactant 5

HCID 684712-Bromo-m-xyleneHCID 2733832Lithium HexamethyldisilazideHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 23080030(Pyrrolidin-3-yl)methanol hydrochlorideHCID 86585896Sodium bicarbonate water

Product 1

HCID 24275467(1-(2,6-Dimethylphenyl)pyrrolidin-3-yl)methanolYield 27.8%

Reagents, catalysts & solvents 3

HCID 1542701,5-Diphenylpenta-1,4-dien-3-one;palladiumCatalystHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 2-bromo-1,3-dimethylbenzene (500 mg), pyrrolidine-3-yl methanol hydrochloride (409 mg), bis(dibenzylideneacetone) palladium (155 mg), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos; 222 mg) in tetrahydrofuran (5 mL), molecular sieves 4A (powder; 410 mg) were added. To the mixed solution, a solution (8.9 mL) of 1.0 M lithium hexamethyldisilazide in tetrahydrofuran was added, and the resultant reaction mixture was heated and refluxed for 2.5 hours. To the reaction solution, saturated sodium bicarbonate water and ethyl acetate were added, and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 75:25), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (154 mg) as a yellow oily substance.

Workup

  1. customthe resultant reaction mixture
  2. temperaturewas heated
  3. temperaturerefluxed for 2.5 hours
  4. customthe resultant reaction mixture
  5. extractionwas extracted with ethyl acetate
  6. washThe organic phase was washed with a saturated saline
  7. dry with materialwas dried over anhydrous sodium sulfate
  8. distillationFrom the organic phase, the solvent was distilled off under reduced pressure
  9. customby purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 75:25)
  10. distillationfrom the resultant, the solvent was distilled off under reduced pressure

Sources & evidence

ORD record
ord-485d3bb5f2b940ad80c6864ebee202d9
Source dataset
uspto-grants-2014_01
Patent number
US08629102B2

Reaction notes

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