Iodine → (S)-methyl 2-(benzyloxycarbonylamino)-3-(1H-indol-5-yl)propanoate

HRID 58853

Reaction equation

HRID 58853 reaction equation
II.[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19]I)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2>CN(C=O)C.[Cl-].[Na+].O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1

Participants

9

Reactant 3

HCID 807IodineHCID 249055-BromoindoleHCID 10915437(R)-2-Benzyloxycarbonylamino-3-iodo-propionic acid methyl ester

Product 1

HCID 117608073(S)-methyl 2-(benzyloxycarbonylamino)-3-(1H-indol-5-yl)propanoateYield 71.4%

Reagents, catalysts & solvents 5

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylCatalystHCID 6228DimethylformamideSolvent3×HCID 57417360Sodium chloride; waterSolvent

Procedure

To a suspension of zinc (2.53 g, 38.8 mmol) in DMF (20 mL) was added I2 (1.10 g, 4.15 mol) followed by addition of a solution of (R)-methyl 2-(benzyloxycarbonylamino)-3-iodopropanoate (4.70 g, 13.0 mmol) in DMF (20 mL). The mixture was stirred at ambient temperature for 5 min and heated at 35° C. for 40 min. Then a solution of 5-bromo-1H-indole (3.00 g, 15.5 mmol) in DMF (10 mL), Pd2(dba)3 (0.25 g, 0.27 mmol) and S—Phos (0.25 g, 0.60 mmol) were added. The reaction mixture was stirred at 50° C. under nitrogen overnight and then cooled to ambient temperature. Brine (500 mL) was added and the resulting mixture was extracted with EtOAc (200 mL×3). The organics were combined, washed with brine (300 mL) and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1 to 5:1) to afford (S)-methyl 2-(benzyloxycarbonylamino)-3-(1H-indol-5-yl)propanoate as a viscous oil (3.27 g, 60% yield).

Workup

  1. temperatureheated at 35° C. for 40 min
  2. stirringThe reaction mixture was stirred at 50° C. under nitrogen overnight
  3. temperaturecooled to ambient temperature
  4. extractionthe resulting mixture was extracted with EtOAc (200 mL×3)
  5. washwashed with brine (300 mL)
  6. concentrationconcentrated
  7. customThe residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1 to 5:1)

Sources & evidence

ORD record
ord-7ddbbc0e8fed4be386b1454272ad4211
Source dataset
uspto-grants-2016_09
Patent number
US09434761B2

Linked notes

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