Nitrogen → HCID 10400115, compound

HRID 1109754Notes

Reaction equation

HRID 1109754 reaction equation
[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[OH-].[K+].[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.N#N>CN(C=O)C.CCOCC>[C:1]([C:4]1[N:5]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2]

Participants

7

Reactant 4

HCID 947NitrogenHCID 96054-FluoroiodobenzeneHCID 14797Potassium HydroxideHCID 72899Indole-2-carboxylic acid

Product 1

HCID 10400115HCID 10400115, compoundYield 51.8%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-carboxy-1H-indole (50 g) in DMF (600 ml) were added potassium hydroxide (40 g) and 4-fluoroiodobenzene (90 g). Reflux in an inert N2 stream for 6 hours. H2O/DMF was distilled off to obtain a constant boiling point of 148° C. After cooling to room temperature ether (500 ml) was added. The precipitated material was filtered off and water (500 ml) was added. Undissolved material was filtered off. To the alkaline water phase was added ethyl acetate (500 ml) and pH was adjusted to 2 by addition of dil. aqueous HCl. The organic phase was worked up as yielding 2-carboxy-1-(4-fluorophenyl)-1H-indole (41 g) which melted at 213° C. The thus obtained carboxyindole (38 g) was added cautiously to a suspension of LiAlH4 (7.5 g) in dry THF (350 ml) at such a rate that the temperature was kept below 50° C. The mixture was finally stirred at 50° C. for 1.5 h. After cooling 5M NaOH solution was added under vigorous stirring. Precipitated inorganic material was filtered off and washed thoroughly with dichloromethane. After evaporation of the combined organic phases 1-(4-fluorophenyl)-2-hydroxymethyl-1H-indole (35 g) was isolated as a crystalline product. Mp: 65°-66° C. The hydroxymethyl derivative (35 g) was dissolved in ethanol (600 ml). The solution was hydrogenated in a Parr apparatus with 15% Pd/C as catalyst at 3 ato. for 20 h. The catalyst was filtered off and ethanol evaporated leaving the crude title compound 23a as an oil. Purification by elution (dichloromehtane/heptane 1:1 as eluent) through silica gel afforded the pure 1-(4-fluorophenyl)-2-methyl-1H-indole (18 g) as a crystalline product. Mp: 43° C.

Workup

  1. distillationH2O/DMF was distilled off
  2. customto obtain a constant boiling point of 148° C
  3. additionwas added
  4. filtrationThe precipitated material was filtered off
  5. additionwater (500 ml) was added
  6. filtrationUndissolved material was filtered off
  7. additionTo the alkaline water phase was added ethyl acetate (500 ml) and pH
  8. additionwas adjusted to 2 by addition of dil. aqueous HCl

Sources & evidence

ORD record
ord-7e0a51270895440f9481fd8070f6659c
Source dataset
uspto-grants-1994_06
Patent number
US05322851

Reaction notes

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