N,N'-Dimethylethylenediamine → 1-[3-hydroxy-5-(pyridin-3-ylamino)-phenyl]-1H-indole-5-carbonitrile

HRID 1784810Notes

Reaction equation

HRID 1784810 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[C:6]([O:8]CC2C=CC(OC)=CC=2)[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:33]([C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH:39]=[CH:38]2)#[N:34].CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[OH:8][C:6]1[CH:7]=[C:2]([N:40]2[C:41]3[C:37](=[CH:36][C:35]([C:33]#[N:34])=[CH:43][CH:42]=3)[CH:38]=[CH:39]2)[CH:3]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=1

Participants

7

Reactant 4

HCID 8070N,N'-DimethylethylenediamineHCID 27513Indole-5-carbonitrileHCID 62657Potassium Phosphate, TribasicHCID 50994028[3-Bromo-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine

Product 1

HCID 688425611-[3-hydroxy-5-(pyridin-3-ylamino)-phenyl]-1H-indole-5-carbonitrileYield 10.8%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

[3-Bromo-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine (193 mg, ca 0.5 mmol) was placed in a 5 mL glass reactor. Copper (I) iodide (0.5 mmol, 96 mg), potassium phosphate (213 mg, 1 mmol), toluene (3 mL), 5-cyanoindole (1.0 mmol, 142 mg) and N,N′-dimethylethylenediamine (53 mg, 0.6 mmol) were added to the reactor, and the sealed reactor was heated to 110° C. for 24 h. After cooling the reaction mixture to room temperature, the solution was filtered through a short pad of Celite®, and the filtrate was concentrated. The residue was extracted with methylene chloride and aqueous sodium bicarbonate solution. The organic layer was dried, concentrated, and the residue was purified by silica gel column (Biotage) using 2% MeOH in methylene chloride. Pure fractions were treated with 10% dimethylsulfide, 50% TFA in methylene chloride for 2 min. The volatiles were evaporated immediately with a stream of nitrogen with mild heating. The residue was purified by passing through a short pad of silica gel using 15% MeOH in methylene chloride as eluent to give 1-[3-hydroxy-5-(pyridin-3-ylamino)-phenyl]-1H-indole-5-carbonitrile (17.5 mg, 0.054 mmol) which solidified on standing. 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=2.4, 1H), 8.00-8.30 (m, 2H), 7.65 (d, J=8.8, 1H), 7.61 (m, 1H), 7.54 (d, J=3.2, 1H), 7.43 (dd, J=8.4, 1.2, 1H), 7.28 (dd, J=8.4, 4.8, 1H), 6.74 (d, J=3.2, 1H), 6.48 (m, 1H), 6.20-6.42 (m, 2H).

Workup

  1. temperatureAfter cooling the reaction mixture to room temperature
  2. filtrationthe solution was filtered through a short pad of Celite®
  3. concentrationthe filtrate was concentrated
  4. extractionThe residue was extracted with methylene chloride and aqueous sodium bicarbonate solution
  5. customThe organic layer was dried
  6. concentrationconcentrated
  7. customthe residue was purified by silica gel column (Biotage)
  8. additionPure fractions were treated with 10% dimethylsulfide, 50% TFA in methylene chloride for 2 min
  9. customThe volatiles were evaporated immediately with a stream of nitrogen with mild heating
  10. customThe residue was purified

Sources & evidence

ORD record
ord-4d26c78cbdef44779b108ae6e7f26c9c
Source dataset
uspto-grants-2009_03
Patent number
US07504401B2

Reaction notes

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