Aniline → 4-methyl-N-((1R,2S)-2-methylcyclohexyl)-6-(phenylamino)-1H-indole-2-carboxamide

HRID 62661Notes

Reaction equation

HRID 62661 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:20])=[O:12])[NH:8]2)=[C:4]([CH3:21])[CH:3]=1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.C(O[K])(C)(C)C.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1(C)C(C)=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][C:4]1[CH:3]=[C:2]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[CH3:20])=[O:12])[NH:8]2

Participants

7

Reactant 4

HCID 6115AnilineHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 732918016-bromo-4-methyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamideHCID 178418922HCID 178418922, compound

Product 1

HCID 735079534-methyl-N-((1R,2S)-2-methylcyclohexyl)-6-(phenylamino)-1H-indole-2-carboxamideYield 31%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 7237O-XyleneSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred solution of 6-bromo-4-methyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide (4AH: 500 mg, 1.43 mmol) in xylene (7.5 mL) were added Pd(OAc)2 (58 mg, 0.26 mmol), JohnPhos (51 mg, 0.17 mmol), tBuOK (644 mg, 5.74 mmol) and aniline (802 mg, 8.62 mmol). The resulting mixture was purged with argon for 10 minutes and then heated at 100° C. for 3 h in sealed tube. The reaction mixture was partitioned between ethyl acetate and water. The organic layer separated and washed with brine and dried over Na2SO4, concentrated. The crude product was purified by column chromatography followed by preparative HPLC to obtain 160 mg of 4-methyl-N-((1R,2S)-2-methylcyclohexyl)-6-(phenylamino)-1H-indole-2-carboxamide (6A: 30%) as an off-white solid.

Workup

  1. customThe resulting mixture was purged with argon for 10 minutes
  2. customThe reaction mixture was partitioned between ethyl acetate and water
  3. customThe organic layer separated
  4. washwashed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe crude product was purified by column chromatography

Sources & evidence

ORD record
ord-f5d8ae6b18cc4fb39193805344825bf0
Source dataset
uspto-grants-2016_09
Patent number
US09447039B2

Reaction notes

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