Dimethylamine → 1-(5-Chloro-1H-indol-3-yl)-N,N-dimethylmethanamine

HRID 323836Notes

Reaction equation

HRID 323836 reaction equation
C=O.[CH3:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[C:16]([O-])(O)=O.[Na+].[OH-].[Na+]>CCO.CC(O)=O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:5](=[CH:14][CH:15]=1)[NH:4][CH:3]=[C:10]2[CH2:11][N:12]([CH3:16])[CH3:13]

Participants

8

Reactant 5

HCID 674DimethylamineHCID 712FormaldehydeHCID 14798Sodium HydroxideHCID 871105-ChloroindoleHCID 516892Sodium Bicarbonate

Product 1

HCID 134914391-(5-Chloro-1H-indol-3-yl)-N,N-dimethylmethanamineYield 85%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 702EthanolSolvent2×

Procedure

A solution of aqueous formaldehyde (37%, 2.95 mL, 66.0 mmol) and dimethylamine (40%, 5.30 mL, 66.0 mmol) in 20 mL EtOH was cooled to 0° C. 5-Chloroindole (4.0 g, 26.4 mmol) was dissolved in a HOAc:EtOH mixture (1:1, 40 mL) and added dropwise to the reaction mixture. After stirring at this temperature for 2 h, the mixture was allowed to warm to room temperature and stir overnight. The mixture was added to a sat'd solution of NaHCO3. 1 N NaOH was added until the pH was between 9-10. The resulting mixture was extracted with CH2Cl2 (3×). The organics were combined and washed with a sat'd aq. NaCl, dried over MgSO4, filtered and concentrated in vacuo to give 4.65 g (85%) of 5-chloro-3-[(dimethylamino)methyl] indole as a yellow powder. Without further purification, 5-chloro-3-[(dimethylamino)methyl] indole (4.65 g, 22.4 mmol) was dissolved in dimethylformamide (80 mL) at room temperature with stirring. To this was added KCN (2.18 g, 33.5 mmol) in H2O (10 mL). The mixture was warmed to 140° C. and stirred for 14 h. H2O was added and the mixture was extracted with EtOAc (2×). The organics were combined and washed with sat'd brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by SiO2 flash chromatography (3:2, Heptane:EtOAc) to give 2.65 g (63%) of 5-chloroindole-3-acetonitrile. 1H NMR (DMSO-d6, 300 MHz) δ 11.30 (br s, 1 H), 7.63 (s, 1 H), 7.42-7.38 (m, 2 H), 7.05 (d, J=6.0 Hz, 1 H), 5.70 (s, 2 H).

Workup

  1. stirringstir overnight
  2. extractionThe resulting mixture was extracted with CH2Cl2 (3×)
  3. washwashed with a sat'd aq. NaCl
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-62489daf78f14d35971b2567c852db80
Source dataset
uspto-grants-2001_04
Patent number
US06214991B1

Reaction notes

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