Toluene → 5-Bromo-3-cyanoindole

HRID 1264243Notes

Reaction equation

HRID 1264243 reaction equation
Cl.[NH2:2]O.[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]=O.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>CO.C(Cl)Cl.C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:14]#[N:2]

Participants

8

Reactant 4

HCID 1140TolueneHCID 24386Thionyl ChlorideHCID 701375-Bromoindole-3-carbaldehydeHCID 443297Hydroxyamine hydrochloride

Product 1

HCID 36233545-Bromo-3-cyanoindoleYield 78.1%

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

Hydroxylamine hydrochloride (4.5 g, 66 mmol) is add to a mixture of 5-bromoindole-3-carbaldehyde (14.7 g, 66 mmol, reference example 74) and methanol (100 mL). After 1 hour toluene (80 mL) and THF (30 mL) are added and the reaction concentrated. Additional toluene (80 mL) is added and the reaction is azeotroped again. The mixture is dissolved in toluene (200 mL) and thionyl chloride (12 mL, 165 mmol) added causing a mild exotherm. The reaction is placed in a 70° C. bath and heated for 45 minutes. The reaction is then cooled and azeotroped with a mixture of CH2Cl2 and THF. The crude reaction mixture is dissolved in a mixture of methanol and CH2Cl2, adsorbed to silica gel and extracted with CH2Cl2 to provide 11.4 g of 5-bromoindole-3-carbonitrile. An analytically pure sample is obtained by recrystallization from toluene: (reddish needles) m.p. 189-191; 1H NMR (300 MHz, DMSO-d6) d 12.38 (bs, 1H), 8.30 (d, J=3.0 Hz, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.6, 1.6 Hz, 1H); MS (EI) m/z 220 (M+, Br).

Workup

  1. concentrationthe reaction concentrated
  2. additionAdditional toluene (80 mL) is added
  3. customthe reaction is azeotroped again
  4. dissolutionThe mixture is dissolved in toluene (200 mL)
  5. customis placed in a 70° C.
  6. temperatureheated for 45 minutes
  7. temperatureThe reaction is then cooled
  8. customazeotroped with a mixture of CH2Cl2 and THF
  9. customThe crude reaction mixture
  10. extractionextracted with CH2Cl2

Sources & evidence

ORD record
ord-0cdabe9f9bda4be28a063878fe199a1a
Source dataset
uspto-grants-2003_04
Patent number
US06541505B1

Reaction notes

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