Iodine → (S)-methyl 3-(3-(benzyloxy)-4-methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate

HRID 58855Notes

Reaction equation

HRID 58855 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14]I)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].II.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH2:47]([O:54][C:55]1[CH:60]=[C:59](Br)[CH:58]=[CH:57][C:56]=1[CH3:62])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>[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].O.CCOC(C)=O.CN(C=O)C>[CH2:47]([O:54][C:55]1[CH:60]=[C:59]([CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH3:13])=[O:11])[CH:58]=[CH:57][C:56]=1[CH3:62])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1

Participants

10

Reactant 4

HCID 807IodineHCID 10903591methyl (2R)-2-(((tert-butoxy)carbonyl)amino)-3-iodopropanoateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 509367922-(Benzyloxy)-4-bromo-1-methylbenzene

Product 1

HCID 117690422(S)-methyl 3-(3-(benzyloxy)-4-methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoateYield 37.1%

Reagents, catalysts & solvents 5

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Dry DMF (100 mL) was added to zinc dust (7.00 g, 108 mmol) in a flame dried flask under N2. (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (9.7 g, 29 mmol) and a catalytic amount of iodine (0.7 g, 2 mmol) were added. The mixture was stirred at ambient temperature for 0.5 h, then Pd2(dba)3 (1.9 g, 2.0 mmol), S—Phos (1.6 g, 4.0 mmol) and 2-(benzyloxy)-4-bromo-1-methylbenzene (7.40 g, 27.0 mmol) were added. The reaction mixture was stirred at 60° C. for 6 h then cooled to ambient temperature. EtOAc (500 mL) and water (500 mL) were added and the organic phase was separated, washed with water (300 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc=10:1) to afford (S)-methyl 3-(3-(benzyloxy)-4-methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (4.0 g, 37% yield).

Workup

  1. customdried flask under N2
  2. stirringThe reaction mixture was stirred at 60° C. for 6 h
  3. temperaturethen cooled to ambient temperature
  4. customthe organic phase was separated
  5. washwashed with water (300 mL×3) and brine (300 mL×1)
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated
  8. customThe residue was purified by flash column chromatography on silica gel (hexane/EtOAc=10:1)

Sources & evidence

ORD record
ord-148188e62f8f40c9b35e0657c7b67b9f
Source dataset
uspto-grants-2016_09
Patent number
US09434761B2

Reaction notes

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