Methyl Isocyanate → 4-Chloro-3-cyanomethyl-indole-1-carboxylic acid methylamide

HRID 489729Notes

Reaction equation

HRID 489729 reaction equation
CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([CH2:26][C:27]#[N:28])=[CH:20][NH:21]2.[CH3:29][N:30]=[C:31]=[O:32]>O1CCCC1>[CH3:29][NH:30][C:31]([N:21]1[C:22]2[C:18](=[C:17]([Cl:16])[CH:25]=[CH:24][CH:23]=2)[C:19]([CH2:26][C:27]#[N:28])=[CH:20]1)=[O:32]

Participants

6

Reactant 4

HCID 12228Methyl IsocyanateHCID 130352,2,6,6-TetramethylpiperidineHCID 43006592-(4-chloro-1H-indol-3-yl)acetonitrileHCID 178418339Butyllithium

Product 1

HCID 235890514-Chloro-3-cyanomethyl-indole-1-carboxylic acid methylamideYield 21%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 2,2,6,6-tetramethyl piperidine (0.18 ml, 1.05 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) was added butyllithium (2.5M in hexanes; 0.42 ml, 1.05 mmol). The reaction was cooled to −78° C. and a solution of (4-chloro-1H-indol-3-yl)-acetonitrile (200 mg, 1.05 mmol) in anhydrous tetrahydrofuran (5 ml) was added, maintaining the temperature between −78° C. and −72° C. After 5 minutes, methyl isocyanate (0.06 ml, 1.05 mmol) was added. The dry ice bath was removed after 15 minutes and the reaction was allowed to stir overnight. After the solvent was removed under reduced pressure, the residue was partitioned between dichloromethane(100 ml) and saturated sodium chloride solution (5 ml). The organic extract was dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane to give 4-chloro-3-cyanomethyl-indole-1-carboxylic acid methylamide as a white solid (54 mg, 21%). 1H NMR (CDCl3) δ: 3.07 (d, 3H, J=4.7 Hz), 4.17 (s, 2H), 7.24 (m, 2H), 7.50 (s, 1H), 8.14 (m, 1H) M+247.

Workup

  1. temperaturemaintaining the temperature between −78° C. and −72° C
  2. customThe dry ice bath was removed after 15 minutes
  3. customAfter the solvent was removed under reduced pressure
  4. customthe residue was partitioned between dichloromethane(100 ml) and saturated sodium chloride solution (5 ml)
  5. extractionThe organic extract
  6. dry with materialwas dried (anhydrous magnesium sulfate)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customPurification by flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane

Sources & evidence

ORD record
ord-3811e634a8234bc7a61b7ba14466894c
Source dataset
uspto-grants-2005_12
Patent number
US06979696B2

Reaction notes

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