5-Bromo-2-chloroanisole → HCID 10295422, compound

HRID 1793448Notes

Reaction equation

HRID 1793448 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH:15]3[CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:22]1[CH:23]=[CH:24][C:25]([Cl:30])=[C:26]([O:28][CH3:29])[CH:27]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:30][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]3[CH:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20]2)=[CH:27][C:26]=1[O:28][CH3:29]

Participants

6

Reactant 3

HCID 27695675-Bromo-2-chloroanisoleHCID 22021984HCID 22021984, compoundHCID 23665647Potassium tert-butoxide

Product 1

HCID 10295422HCID 10295422, compound

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

A quantity of 0.85 g (3.0 mmoles, 1 eq) of 6-(3,4-dimethoxy-phenyl)-octahydropyrido[1,2-a]pyrazine and 0.76 g (3.4 mmoles, 1.1 eq) of 5-bromo-2-chloro-anisole is dissolved in 25 mL of anhydrous toluene, and the solution is purged with N2 for 20 min. To the solution is added 0.18 g (0.30 mmoles, 0.10 eq) of rac-2, 2′-Bis(diphenyl-phosphino)-1,1′-binapphtyl, 0.14 g (0.15 mmole, 0.05 eq) of Tris(dibenzylideneacetone)-dipalladium(0) and 0.52 g (4.6 mmoles, 1.5 eq) of Potassium tert-butoxide in order. The mixture is heated at 80° C. under N2 overnight. After it is cooled down, the reaction is filtered through Celite. The organic solution is washed with 1N NaOH and brine, dried over Na2SO4 and concentrated. The residue is purified by flash chromatography on silica gel eluted with 50:1 dichloromethane: methanol to afford 2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a] pyrazine (compound 5) as a brownish stick solid (0.85 g, 68%). Analysis: 1H NMR (300 MHz, CDCl3): 7.16 (1H, d), 6.80 (3H, m), 6.40 (2H, m). 3.88 (3H, s), 3.86 (3H, s), 3.85 (3H, s), 3.40 (2H, m), 2.95 (1H, m), 2.70 (3H, m), 2.30 (1H, m), 2.00 (1H, m), 1.82˜1.40 (6H, m). MS (LC-MS): Calculated for C23H29ClN2O3 416.94, found 417.23 (M+1).

Workup

  1. customthe solution is purged with N2 for 20 min
  2. temperatureAfter it is cooled down
  3. filtrationthe reaction is filtered through Celite
  4. washThe organic solution is washed with 1N NaOH and brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue is purified by flash chromatography on silica gel
  8. washeluted with 50:1 dichloromethane

Sources & evidence

ORD record
ord-913878cf886e4fed88af97f8d493ec75
Source dataset
uspto-grants-2006_07
Patent number
US07081458B2

Reaction notes

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