Hexamethyldisilazane → 1-(4-Methylphenyl)-4-[2-(6-aminocarbonylisochroman-1-yl)ethyl]piperazine

HRID 1417849Notes

Reaction equation

HRID 1417849 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[C:25]4[C:20](=[CH:21][C:22](Br)=[CH:23][CH:24]=4)[CH2:19][CH2:18][O:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=[O:57].C[Si](C)(C)N[Si](C)(C)C.C([N:70]([CH:73](C)C)CC)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[C:25]4[C:20](=[CH:21][C:22]([C:73]([NH2:70])=[O:57])=[CH:23][CH:24]=4)[CH2:19][CH2:18][O:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1

Participants

9

Reactant 5

HCID 13838HexamethyldisilazaneHCID 812191,3-Bis(diphenylphosphino)propaneHCID 81531DiisopropylethylamineHCID 232889161-(4-Methylphenyl)-4-[2-(6-bromoisochroman-1-yl)ethyl]piperazineHCID 178418416HCID 178418416, compound

Product 1

HCID 232887821-(4-Methylphenyl)-4-[2-(6-aminocarbonylisochroman-1-yl)ethyl]piperazine

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

An oven dried 5 ml micro vial, equipped with a Claisen condenser, water cooled condenser, and hose adapter, is charged with 1-(4-methylphenyl)-4-[2-(6-bromoisochroman-1-yl)-ethyl]piperazine (CXXVI, EXAMPLE 127, 103 mg, 0.25 mmol), palladium acetate (98%, 2.9 mg, 0.012 mmol) and 1,3-bis-diphenylphosphinopropane (97%, 6.4 mg, 0.015 mmol). Carbon monoxide atmosphere is established in the vial. To the reaction vessel is introduced via syringe DMF (0.62 ml), 1,1,1,3,3,3-hexamethyldisilazane (98%, 0.38 ml, 1.8 mmol), and diisopropylethylamine (0.087 ml, 0.5 mmol). The mixture is heated to 100° over 18 hr. After cooling to 20°-25°, the reaction mixture separates into two phases. The reaction mixture is poured into methylene chloride (pH=12). The mixture is washed one time with aqueous sodium hydroxide (1N). The organic phase is then concentrated under reduced pressure to remove excess solvents and reactants. The residue is dissolved in methylene chloride again and the mixture is washed twice with aqueous hydrochloric acid (1N). The aqueous acidic phases are combined, made basic with concentraged aqueous sodium hydroxide (pH>14). The basic mixture is extracted four times with methylene chloride, the organics phases are combined and concentrated. The product crystallized out of the crude and the mother liquor is purified by flash chromatography (silica gel, 13 g; eluting with methanol/ethyl acetate (10/90) to give additional title compound, HRMS Calcd for C23H29N3O2 =379.2260, found=379.2269.

Workup

  1. customAn oven dried 5 ml micro vial
  2. customequipped with a Claisen condenser, water cooled condenser, and hose adapter
  3. temperatureThe mixture is heated to 100° over 18 hr
  4. temperatureAfter cooling to 20°-25°
  5. washThe mixture is washed one time with aqueous sodium hydroxide (1N)
  6. concentrationThe organic phase is then concentrated under reduced pressure
  7. customto remove excess solvents and reactants
  8. dissolutionThe residue is dissolved in methylene chloride again
  9. washthe mixture is washed twice with aqueous hydrochloric acid (1N)
  10. extractionThe basic mixture is extracted four times with methylene chloride
  11. concentrationconcentrated
  12. customThe product crystallized out of the crude
  13. customthe mother liquor is purified by flash chromatography (silica gel, 13 g
  14. washeluting with methanol/ethyl acetate (10/90)

Sources & evidence

ORD record
ord-f5bb4aaf432144f59576f24c7e6d042f
Source dataset
uspto-grants-1999_03
Patent number
US05877317

Reaction notes

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