Iodine → (2R)-2-tert-butoxycarbonylamino-5-(3-fluorophenyl)-5-oxo-pentanoic acid methyl ester

HRID 853780Notes

Reaction equation

HRID 853780 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Mg].II.[CH3:12][O:13][C:14](=[O:28])[C@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1>[CH3:12][O:13][C:14](=[O:28])[C@H:15]([NH:16][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:18][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1)=[O:20]

Participants

6

Reactant 4

HCID 807IodineHCID 140821-Bromo-3-fluorobenzeneHCID 5462224Magnesium2×HCID 112650211-tert-Butyl 2-methyl (2R)-5-oxopyrrolidine-1,2-dicarboxylate

Product 1

HCID 69474896(2R)-2-tert-butoxycarbonylamino-5-(3-fluorophenyl)-5-oxo-pentanoic acid methyl esterYield 51%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a mixture of 1-bromo-3-fluorobenzene (0.79 g, 4.5 mmol) and magnesium turnings (0.12 g, 5.0 mmol) in anhydrous THF (8 mL) was added a small piece of iodine. The mixture was heated at reflux for 2 hr and no magnesium turnings left. The solution was cooled to 0° C. and transferred into a stirred solution of N-Boc-D-pyroglutamic acid methyl ester (0.80 g, 3.3 mmol) in anhydrous THF (4 mL) at −40° C. under argon atmosphere. After stirring at −40° C. for 1 hr and then at 0° C. for 1 hr, the reaction was quenched with 8 mL of 1:1 HOAc/MeOH and the mixture diluted with Et2O (40 mL). The organic layers were washed with water and brine, dried (Na2SO4) and concentrated under vacuum. Purification by silica gel chromatography (10–20% EtOAc/hexanes) gave 0.57 g (51%) of (2R)-2-tert-butoxycarbonylamino-5-(3-fluoro-phenyl)-5-oxo-pentanoic acid methyl ester as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.82 (1H, d), 7.75 (1H, d), 7.56 (1H, q), 7.38 (1H, t), 5.30 (1H, br.d), 4.50 (1H, br.s), 3.87 (3H, s), 3.20 (2H, m), 2.45 (1H, m), 2.20 (1H, m), 1.54 (9H, s).

Workup

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 2 hr
  3. waitat 0° C. for 1 hr
  4. customthe reaction was quenched with 8 mL of 1:1 HOAc/MeOH
  5. additionthe mixture diluted with Et2O (40 mL)
  6. washThe organic layers were washed with water and brine
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated under vacuum
  9. customPurification by silica gel chromatography (10–20% EtOAc/hexanes)

Sources & evidence

ORD record
ord-e2069847dfa34698ab6d346937692e85
Source dataset
uspto-grants-2007_08
Patent number
US07256186B2

Reaction notes

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