Toluene → HCID 178429921, compound

HRID 900456Notes

Reaction equation

HRID 900456 reaction equation
Br[C:2]1[CH:9]=[C:8]([N:10]2[C:18]3[CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]=3[C:12]([CH3:22])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1.CC(C)([O-:34])C.[Na+].C1(C)C=CC=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CS(C)=O.C(O)C>[OH:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:23][C:2]2[CH:9]=[C:8]([N:10]3[C:18]4[CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]=4[C:12]([CH3:22])=[CH:11]3)[CH:7]=[CH:6][C:3]=2[C:4]([NH2:5])=[O:34])[CH2:25][CH2:26]1

Participants

9

Reactant 4

HCID 1140TolueneHCID 118539082-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrileHCID 23676156Sodium t-butoxideHCID 178511715HCID 178511715, compound

Product 1

HCID 178429921HCID 178429921, compoundYield 47%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 962WaterSolventHCID 22338741Dimethylsulfoxide ethanolSolvent

Conditions

Temperature
115 °C

Procedure

A “Personal Chemistry” microwave vial was charged with the title compound of Example 2 [2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile (1.072 g, 3.0 mmol)], trans-4-aminocyclohexanol (1.382 g, 12.0 mmol), palladium (II) acetate (33.7 mg, 5 mol %), 1,1′-bis(diphenylphosphino)ferrocene (DPPF) (166.3 mg, 10 mol %), and sodium tert-butoxide (576.7 mg, 6.0 mmol). To this was added toluene (20 mL) and the reaction was heated with microwave irradiation to 115° C. for 15 min. After allowing the reaction vessel to cool, a suspension formed and was filtered and the filtrate evaporated. The residue was purified by flash chromatography. The intermediate product was hydrolyzed by dissolution in 25% dimethylsulfoxide/ethanol, adding 0.5 mL of 1 N sodium hydroxide and 0.5 mL of 30% aqueous hydrogen peroxide, followed by stirring at room temperature for 4 hours. After judging the reaction to be complete by TLC, the DMSO/ethanol mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were washed with brine (2×), dried over Na2SO4, and evaporated. The compound was purified by column chromatography eluting with EtOAc-MeOH to yield 575 mg (47% yield) of the title compound as a white powder. LCMS m/z: (M+H)=410.3

Workup

  1. temperatureto cool
  2. customa suspension formed
  3. filtrationwas filtered
  4. customthe filtrate evaporated
  5. customThe residue was purified by flash chromatography
  6. dissolutionThe intermediate product was hydrolyzed by dissolution in 25% dimethylsulfoxide/ethanol
  7. additionadding 0.5 mL of 1 N sodium hydroxide and 0.5 mL of 30% aqueous hydrogen peroxide
  8. customthe reaction
  9. extractionextracted with ethyl acetate (3×)
  10. washThe combined organics were washed with brine (2×)
  11. dry with materialdried over Na2SO4
  12. customevaporated
  13. customThe compound was purified by column chromatography
  14. washeluting with EtOAc-MeOH

Sources & evidence

ORD record
ord-f74026fff9de41d3bd5f7adfa6dd63d4
Source dataset
uspto-grants-2008_04
Patent number
US07358370B2

Reaction notes

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