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

HRID 1499669Notes

Reaction equation

HRID 1499669 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]([CH3:35])=[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)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]>[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]([CH3:35])=[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 866667971-(5-Chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone

Product 1

HCID 86666842tert-Butyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylateYield 55.1%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
60 °C

Procedure

Zinc (1.71 g, 26.2 mmol) was suspended in N,N-dimethylformamide (45.0 mL) and 1,2-dibromoethane (210 μL, 2.5 mmol) was added. The mixture was heated at 60° C. for 10 minutes and then cooled to room temperature. Chlorotrimethylsilane (330 μL, 2.6 mmol) was added and stirred at 60° C. for 10 minutes and cooled to room temperature. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (from Oakwood, 6.25 g, 22.1 mmol) in N,N-dimethylformamide (5.0 mL) was then added and the mixture stirred at room temperature for 1 hour. 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (5.00 g, 15.4 mmol), tri-(2-furyl)phosphine (358 mg, 1.54 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.70 g, 0.77 mmol) were added in order and the reaction mixture was warmed to 70° C. and stirred overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate (EtOAc) and sat. NH4Cl solution. The layers were separated and the aqueous extracted further with EtOAc (2×). The combined organics were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0-30% EtOAc in hexanes to give 3.0 g (55%) of the desired product as an orange solid. LCMS calculated for C18H24ClNO4Na (M+Na)+: m/z=376.1; Found: 376.0. 1H NMR (400 MHz, CDCl3): δ 7.52 (s, 1H), 4.32, (m, 2H), 4.16 (m, 3H), 3.66 (s, 3H), 2.59 (s, 3H), 2.31 (s, 3H), 1.45 (s, 9H) ppm.

Workup

  1. temperaturecooled to room temperature
  2. temperaturecooled to room temperature
  3. stirringthe mixture stirred at room temperature for 1 hour
  4. temperaturethe reaction mixture was warmed to 70° C.
  5. stirringstirred overnight
  6. temperatureThe mixture was cooled to room temperature
  7. custompartitioned between ethyl acetate (EtOAc) and sat. NH4Cl solution
  8. customThe layers were separated
  9. extractionthe aqueous extracted further with EtOAc (2×)
  10. washThe combined organics were washed with water and brine
  11. dry with materialdried over MgSO4
  12. concentrationconcentrated
  13. customThe residue was purified on silica gel
  14. washeluting with 0-30% EtOAc in hexanes

Sources & evidence

ORD record
ord-c59ae1f7dad146feac25139be91ba064
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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