Chlorotrimethylsilane → 3-[1-(4-difluoromethoxy-benzenesulfonyl)-1H-indol-5-yl]azetidine-1-carboxylic acid tert-butyl ester

HRID 1890365Notes

Reaction equation

HRID 1890365 reaction equation
C[Si](C)(C)Cl.BrC(Br)C.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[F:22][CH:23]([F:44])[O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[C:42]3[C:37](=[CH:38][C:39](I)=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>CC(N(C)C)=O.[Zn].[Cu]I>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH:23]([F:44])[F:22])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[CH:35]=[CH:36]3)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]

Participants

8

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 112011,1-DibromoethaneHCID 11000522Tert-butyl 3-iodoazetidine-1-carboxylateHCID 685969371-(4-difluoromethoxybenzenesulfonyl)-5-iodo-1H-indole

Product 1

HCID 685981673-[1-(4-difluoromethoxy-benzenesulfonyl)-1H-indol-5-yl]azetidine-1-carboxylic acid tert-butyl esterYield 93.6%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 31374DimethylacetamideSolvent3×

Conditions

Temperature
65 °C

Procedure

In an inert atmosphere, zinc dust (300 mg, 4.59 mmol) was vigorously stirred in dimethylacetamide (1.6 ml) and heated to 65° C. Subsequently, trimethylchlorosilane (70 μl, 0.57 mmol) and dibromoethane (50 μl, 0.57 mmol) were added to the reaction mixture, and the reaction mixture was stirred for another 30 minutes at 65° C. 3-Iodo-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.53 mmol) in dimethylacetamide (2 ml) was added dropwise to the above prepared solution at 65° C., and then the reaction mixture was allowed to cool to room temperature. 1-(4-Difluoromethoxy-benzenesulfonyl)-5-iodo-1H-indole (961 mg, 2.12 mmol) in dimethylacetamide (4 ml) was added to the reaction mixture. Subsequently, [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichlormethane (52.4 mg, 0.06 mmol) and copper(I)iodide (24.4 mg, 0.13 mmol) were added. The reaction mixture was heated to 80° C. for 1 hour, before it was cooled to room temperature and quenched with water (150 ml). Ammonium chloride (2 g) was added and the reaction mixture was extracted twice with diethylether (150 ml). The organic layer was dried over magnesium sulphate, filtered, and the solvent was evaporated under reduced pressure to give an oil (950 mg). The crude product was purified by silica gel chromatography with dichloromethane as eluent, yielding the purified product (553 mg, 52%). ESI-MS [m/z]: 423.05 [M-(C4H9)+H]+.

Workup

  1. temperatureto cool to room temperature
  2. temperatureThe reaction mixture was heated to 80° C. for 1 hour, before it
  3. temperaturewas cooled to room temperature
  4. customquenched with water (150 ml)
  5. additionAmmonium chloride (2 g) was added
  6. extractionthe reaction mixture was extracted twice with diethylether (150 ml)
  7. dry with materialThe organic layer was dried over magnesium sulphate
  8. filtrationfiltered
  9. customthe solvent was evaporated under reduced pressure

Sources & evidence

ORD record
ord-de096f5d8d5d47f58a8e5235ee9ceae9
Source dataset
uspto-grants-2013_08
Patent number
US08507469B2

Reaction notes

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