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

HRID 510934Notes

Reaction equation

HRID 510934 reaction equation
BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1.[Cl:25][C:26]1[C:27]([CH3:38])=[C:28](I)[C:29]([O:35][CH3:36])=[C:30]([C:32](=[O:34])[CH3:33])[CH:31]=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].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[C:32]([C:30]1[C:29]([O:35][CH3:36])=[C:28]([CH:11]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:12]2)[C:27]([CH3:38])=[C:26]([Cl:25])[CH:31]=1)(=[O:34])[CH3:33]

Participants

9

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 16244498Benzyl 3-iodoazetidine-1-carboxylateHCID 866667971-(5-Chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone

Product 1

HCID 86666850Benzyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylateYield 44%

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 521585Tris(furan-2-yl)phosphaneCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent3×

Conditions

Temperature
70 °C

Procedure

Zinc (1.15 g, 17.6 mmol) was suspended with 1,2-dibromoethane (0.101 mL, 1.17 mmol) in DMF (21 mL). The mixture was heated at 70° C. for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.149 mL, 1.17 mmol) was added dropwise and stirring was continued for 1 hour. A solution of benzyl 3-iodoazetidine-1-carboxylate (4.6 g, 15 mmol, from Pharmablock) in DMF (20 mL) was then added and the mixture was heated at 40° C. for 1 h before a mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (5.0 g, 15 mmol, from Example 60, Step 2), tris(dibenzylideneacetone)dipalladium(0) (0.27 g, 0.29 mmol) and tri-(2-furyl)phosphine (0.14 g, 0.59 mmol) in DMF (40 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 20% EtOAc in hexane) to give the desired product (2.5 g, 44%). LCMS calculated for C21H23ClNO4 (M+H)+: m/z=338.1. found: 388.1.

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 20% EtOAc in hexane)

Sources & evidence

ORD record
ord-0ba66419aa8243949fcbcd558248f973
Source dataset
uspto-grants-2015_08
Patent number
US09096600B2

Reaction notes

Loading…