Dimethylformamide → 2-Amino-4-bromo-5-methylbenzonitrile

HRID 523245Notes

Reaction equation

HRID 523245 reaction equation
[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[CH3:11][N:12](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:6]1[CH:8]=[C:2]([Br:1])[C:3]([CH3:10])=[CH:4][C:5]=1[C:11]#[N:12]

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 1177764315-Bromo-2-iodo-4-methylaniline

Product 1

HCID 1177609322-Amino-4-bromo-5-methylbenzonitrileYield 83%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 5-bromo-2-iodo-4-methylaniline (5.25 g, 16.8 mmol) and zinc cyanide (0.988 g, 8.41 mmol) in DMF (80 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with tetrakis(triphenylphosphine)palladium (0.972 g, 0.841 mmol) and heated at 90° C. overnight. The cooled mixture was diluted with EtOAc and washed sequentially with 10% aqueous LiCl (twice) and brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%), to give a brown solid. The residue was further purified by trituration with MeOH to give three crops of solid. The filtrate was again purified by column chromatography on silica gel, eluting with EtOAc-hexanes (5%, then 10%). The resulting solid was combined with the other crops to provide 2-amino-4-bromo-5-methylbenzonitrile as a tan solid (2.95 g, 83% yield). Mass spectrum m/z 211, 213 (M+H)+.

Workup

  1. customevacuate-fill cycles with nitrogen
  2. washwashed sequentially with 10% aqueous LiCl (twice) and brine
  3. extractionThe aqueous layers were extracted with EtOAc
  4. customthe combined organic layers were dried
  5. concentrationconcentrated
  6. customThe residue was purified by column chromatography on silica gel
  7. washeluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%),
  8. customto give a brown solid
  9. customThe residue was further purified by trituration with MeOH
  10. customto give three crops of solid
  11. customThe filtrate was again purified by column chromatography on silica gel
  12. washeluting with EtOAc-hexanes (5%

Sources & evidence

ORD record
ord-e33929b55ede4a44932c6c9b069e0fc5
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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