Acetic Anhydride → 1-Acetyl-2-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-indole

HRID 1188419Notes

Reaction equation

HRID 1188419 reaction equation
[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.[BH3-]C#N.[Na+].[CH3:19][C:20](OC(C)=O)=[O:21]>CC(O)=O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])(=[O:21])[CH3:19]

Participants

7

Reactant 3

HCID 7918Acetic AnhydrideHCID 5003444Sodium cyanoborohydrideHCID 196970222-methyl-4-(trifluoromethyl)-1H-indole

Product 1

HCID 578001261-Acetyl-2-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-indoleYield 42.6%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 2-methyl-4-(trifluoromethyl)-1H-indole (Example 114D) (0.48 g, 2.41 mmol) was dissolved in HOAc (3.0 mL), cooled to 0° C. and NaBH3CN (0.454 g, 7.23 mmol) was added in one portion. After 5 min the mixture was removed from the cooling bath and stirred at rt for 14 h. The mixture cooled to 0° C. and the pH was adjusted to ca. 13 by addition of 1 N NaOH (20 mL) and further addition of solid NaOH pellets. The mixture was extracted with Et2O (×3), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in dry CH2Cl2 (10 mL) and treated with DMAP (0.884 g, 7.23 mmol). The mixture was cooled to 0° C. and Ac2O (0.455 mL, 4.81 mmol) was added dropwise via syringe. The mixture was stirred overnight, slowly warming to rt, diluted with CH2Cl2, washed (10% HCl, H2O, brine), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.25 g of the title compound as a pale yellow oil: MS (ES) m/z 244 (M+1).

Workup

  1. customAfter 5 min the mixture was removed from the cooling bath
  2. temperatureThe mixture cooled to 0° C.
  3. additionthe pH was adjusted to ca. 13 by addition of 1 N NaOH (20 mL) and further addition of solid NaOH pellets
  4. extractionThe mixture was extracted with Et2O (×3)
  5. washcombined organics were washed (H2O, brine)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. dissolutionThe residue was dissolved in dry CH2Cl2 (10 mL)
  10. temperatureThe mixture was cooled to 0° C.
  11. stirringThe mixture was stirred overnight
  12. temperatureslowly warming to rt
  13. washwashed (10% HCl, H2O, brine)
  14. dry with materialdried over Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated in vacuo
  17. customThe residue was purified by flash chromatography (EtOAc/hexanes)

Sources & evidence

ORD record
ord-a39b7045d5864df6b38aed869ac45aa9
Source dataset
uspto-grants-2014_03
Patent number
US08673948B2

Reaction notes

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