Dimethylformamide → methyl 6-cyano-1-isopropyl-3-methyl-1H-indole-4-carboxylate

HRID 62421Notes

Reaction equation

HRID 62421 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[C:19]([Zn]C#N)#[N:20].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:19]([C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1)#[N:20]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 10340Sodium CarbonateHCID 67464634methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylateHCID 178514179HCID 178514179, compound

Product 1

HCID 67467281methyl 6-cyano-1-isopropyl-3-methyl-1H-indole-4-carboxylateYield 38.9%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolvent

Procedure

To a 10 ml microwave vial was added methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (500 mg, 1.612 mmol), dicyanozinc (150 mg, 1.277 mmol) and DMF (5 mL). The mixture was degassed and stirred at rt under N2 for 15 min. To the mixture was added palladium tetrakis (118 mg, 0.102 mmol) and the reaction was stirred at 95° C. for 1 h. The reaction was allowed to cool and poured into saturated aqueous Na2CO3 (50 mL) and EtOAc (50 mL) and stirred for 20 min. The mixture was extracted with ether (100 ml) and EtOAc (100 ml) (1:1), followed by filtration and evaporation to yield a residue. The residue was purified by silica gel chromatography (Analogix IF280, 0-8% EtOAc/hexanes, SF25-40 g, 30 minutes) to give methyl 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (130 mg, 0.497 mmol, 38.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (d, J=1.52 Hz, 1H) 7.82 (s, 1H) 7.71 (d, J=1.52 Hz, 1H) 4.85-4.97 (m, 1H) 3.90 (s, 3H) 2.29 (s, 3H) 1.45 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 257.4.

Workup

  1. customThe mixture was degassed
  2. stirringthe reaction was stirred at 95° C. for 1 h
  3. temperatureto cool
  4. stirringstirred for 20 min
  5. extractionThe mixture was extracted with ether (100 ml) and EtOAc (100 ml) (1:1)
  6. filtrationfollowed by filtration and evaporation
  7. customto yield a residue
  8. customThe residue was purified by silica gel chromatography (Analogix IF280, 0-8% EtOAc/hexanes, SF25-40 g, 30 minutes)

Sources & evidence

ORD record
ord-47bdf07999ec4a51b56a2b0f8f424319
Source dataset
uspto-grants-2016_09
Patent number
US09446041B2

Reaction notes

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