3-Oxo-azetidine-1-carboxylic acid tert-butyl ester → tert-Butyl 5'-bromo-3'h-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate

HRID 1483924Notes

Reaction equation

HRID 1483924 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH2:9]Cl)[CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[C:18]([N:25]1[CH2:28][C:27](=[O:29])[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:27]1([CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:28]1)[O:29][CH2:9]2

Participants

5

Reactant 3

HCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 706632554-Bromo-2-(chloromethyl)-1-iodobenzeneHCID 178461733HCID 178461733, compound

Product 1

HCID 66555337tert-Butyl 5'-bromo-3'h-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylateYield 77.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-15 °C

Procedure

To a solution of 4-bromo-2-(chloromethyl)-1-iodobenzene (2.0 g, 6.04 mmol, 1 eq) in THF (16 mL), isopropylmagnesium chloride lithium chloride complex (5.11 mL, 1.3M in THF, 1.1 eq) was added over about 5 min while the internal temperature didn't exceed −15° C. Reaction is stirred at −15° C. for 30 min. Then a solution of 1-Boc-3-azetidinone (1.24 g, 1.2 eq) in THF (4 mL) was added dropwise; internal temperature at −30° C. The reaction is stirred at room temperature overnight. Reaction was quenched with a solution of citric acid (14 mL of 1M). This was extracted with MTBE and organic layer was washed with aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude yellow oil is submitted to silica gel column chromatography (0 to 50% ethyl acetate in heptane). 1.6 g of tert-butyl 5′-bromo-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate was obtained.

Workup

  1. customexceed −15° C
  2. customReaction
  3. customat −30° C
  4. stirringThe reaction is stirred at room temperature overnight
  5. customReaction
  6. customwas quenched with a solution of citric acid (14 mL of 1M)
  7. extractionThis was extracted with MTBE and organic layer
  8. washwas washed with aqueous NaHCO3 and brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-956a7748ca794f8f9730a58dfc012ef4
Source dataset
uspto-grants-2016_08
Patent number
US09420793B2

Reaction notes

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