Iodine → 2-(2-Cyclopropyl-6-fluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

HRID 586700

Reaction equation

HRID 586700 reaction equation
[CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].II.[F:8][C:9]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19](F)[C:10]=1[C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=O>O1CCCC1>[CH:1]1([C:19]2[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=[C:9]([F:8])[C:10]=2[C:11]2[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)[CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 807IodineHCID 78037BromocyclopropaneHCID 5462224MagnesiumHCID 223353682,6-Difluoro-N-(2-hydroxy-1,1-dimethylethyl)-4-methoxybenzamide

Product 1

HCID 223352852-(2-Cyclopropyl-6-fluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazoleYield 98%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of cyclopropyl bromide (12.1 g, 100 mmol) in anhydrous tetrahydrofuran (100 mL) was added magnesium turnings (2.4 g, 100 mmol) followed by a crystal of iodine, at room temperature. After a few minutes the reaction initiated and came to reflux without any additional heating. When the reflux was complete the reaction was cooled to room temperature and stirred for 2 hours. A solution of the fluoro compound from preparation 2 (9.64 g, 40 mmol) in tetrahydrofuran (50 mL) was cooled in an ice-bath to 0° C., and the grignard solution (50 mL) was added dropwise over 15 minutes, the cooling bath was removed and reaction warmed to room temperature and stirred for 1 hour. Further grignard solution (20 mL) was added and stirred for 1 hour. Further grignard solution (10 mL) was added and stirred for 1 hour. The reaction mixture was then quenched with 1M citric acid (30 mL), as some solid remained undissolved 2M hydrochloric acid (30 mL) was added. The resultant mixture was partitioned between ethyl acetate (400 mL) and water (200 mL), basified with concentrated ammonia solution and the organic layer separated, washed with water (150 mL), brine (150 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with hexane:isopropyl alcohol 85:15) to give the title compound as a clear oil (10.32 g, 98%).

Workup

  1. waitAfter a few minutes the reaction initiated
  2. temperatureto reflux without any additional heating
  3. temperaturewas cooled in an ice-bath to 0° C.
  4. customthe cooling bath was removed
  5. customreaction
  6. temperaturewarmed to room temperature
  7. stirringstirred for 1 hour
  8. stirringstirred for 1 hour
  9. stirringstirred for 1 hour
  10. customThe reaction mixture was then quenched with 1M citric acid (30 mL), as some solid
  11. additionwas added
  12. customThe resultant mixture was partitioned between ethyl acetate (400 mL) and water (200 mL)
  13. customthe organic layer separated
  14. washwashed with water (150 mL), brine (150 mL)
  15. dry with materialdried (MgSO4)
  16. concentrationconcentrated under reduced pressure
  17. customThe residue was purified by flash chromatography on silica gel (eluting with hexane:isopropyl alcohol 85:15)

Sources & evidence

ORD record
ord-74ea90af8cdc46f5917ea6222893b08d
Source dataset
uspto-grants-2005_08
Patent number
US06936619B2

Linked notes

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