Chlorotrimethylsilane → tert-Butyl 3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate

HRID 510944Notes

Reaction equation

HRID 510944 reaction equation
BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[Cl:22][C:23]1[C:24]([F:35])=[C:25](I)[C:26]([O:32][CH3:33])=[C:27]([C:29](=[O:31])[CH3:30])[CH:28]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C=O)C.[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]>[C:29]([C:27]1[C:26]([O:32][CH3:33])=[C:25]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:24]([F:35])=[C:23]([Cl:22])[CH:28]=1)(=[O:31])[CH3:30]

Participants

9

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 521585Tris(furan-2-yl)phosphaneHCID 11000522Tert-butyl 3-iodoazetidine-1-carboxylateHCID 866668581-(5-Chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone

Product 1

HCID 86666859tert-Butyl 3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylateYield 25.7%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent3×

Conditions

Temperature
70 °C

Procedure

Zinc (0.682 g, 10.4 mmol) was suspended with 1,2-dibromoethane (0.060 mL, 0.69 mmol) in DMF (12 mL). The mixture was heated at 70° C. for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.088 mL, 0.69 mmol) was added dropwise and stirring was continued for 1 hour. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (2.5 g, 8.7 mmol, from Oakwood) in DMF (10 mL) was then added and the mixture was heated at 40° C. for 1 h before a mixture of 1-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone (3.0 g, 9.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.16 g, 0.17 mmol) and tri-(2-furyl)phosphine (0.081 g, 0.35 mmol) in DMF (20 mL) was added. The reaction mixture was warmed to 70° C. and stirred overnight. The mixture was then cooled to room temperature and partitioned between ether and sat. NH4Cl solution. The organic layer was washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 25% EtOAc in hexanes) to give the desired product (0.8 g). LCMS calculated for C17H21ClFNO4Na (M+Na)+: m/z=380.1. found: 380.1.

Workup

  1. temperaturecooled to room temperature
  2. additionwas added
  3. temperatureThe reaction mixture was warmed to 70° C.
  4. stirringstirred overnight
  5. temperatureThe mixture was then cooled to room temperature
  6. custompartitioned between ether and sat. NH4Cl solution
  7. washThe organic layer was washed with water
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated
  10. custompurified on silica gel (eluting with 0 to 25% EtOAc in hexanes)

Sources & evidence

ORD record
ord-73cf9c05634a40cf9254824c3f1ecbfb
Source dataset
uspto-grants-2015_08
Patent number
US09096600B2

Reaction notes

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