Iodine → Methyl (S)-2-(Boc-amino)-3-(4-chloro-3-fluorophenyl)propanoate

HRID 625873Notes

Reaction equation

HRID 625873 reaction equation
II.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16]I)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].C1(P(C2CCCCC2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[C:36](OC)=[CH:35][CH:34]=[CH:33][C:32]=2OC)CCCCC1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51](I)=[CH:50][C:49]=1[F:55]>CCOC(C)=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].CN(C=O)C>[CH:33]1[C:32]2[CH:6]([CH2:3][O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:51]3[CH:52]=[CH:53][C:48]([Cl:47])=[C:49]([F:55])[CH:50]=3)[C:12]([OH:14])=[O:13])=[O:9])[C:25]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]=2[CH:36]=[CH:35][CH:34]=1.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:51]1[CH:52]=[CH:53][C:48]([Cl:47])=[C:49]([F:55])[CH:50]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]

Participants

10

Reactant 4

HCID 807Iodine2×HCID 27365631-Chloro-2-fluoro-4-iodobenzeneHCID 10903591methyl (2R)-2-(((tert-butoxy)carbonyl)amino)-3-iodopropanoateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

Product 2

HCID 57634211Methyl (S)-2-(Boc-amino)-3-(4-chloro-3-fluorophenyl)propanoateHCID 90457412N-Fmoc-3-fluoro-4-chloro-L-phenylalanine

Reagents, catalysts & solvents 4

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

Procedure

To an oven dried 8 mL vial with teflon cap purged with N2 was added Zinc dust (298 mg, 4.56 mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (62.4 mg, 0.152 mmol), 1-chloro-2-fluoro-4-iodobenzene (584 mg, 2.279 mmol), and the reaction mixture was stirred at room temperature for 16 h. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed using four aqueous washes. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and the crude product was purified by silica gel chromatography using 100% hexanes to 30% EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoate, 0.220 g; purity, 93% by LCMS analysis. Analysis LCMS condition F: rt=2.59 min; ESI-MS(+) m/z 332.2 (M+H).

Workup

  1. dry with materialTo an oven dried 8 mL vial with teflon
  2. customcap
  3. custompurged with N2
  4. customDMF was removed
  5. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customthe crude product was purified by silica gel chromatography

Sources & evidence

ORD record
ord-d5271a8fb6974ac9840d62ab4eab7540
Source dataset
uspto-grants-2016_04
Patent number
US09308236B2

Reaction notes

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