Chlorotrimethylsilane → 3-(5-Nitro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

HRID 1260230Notes

Reaction equation

HRID 1260230 reaction equation
BrCCBr.C[Si](Cl)(C)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].Br[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1>C1COCC1.[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:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]

Participants

9

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 782402-Bromo-5-nitropyridineHCID 11000522Tert-butyl 3-iodoazetidine-1-carboxylate

Product 1

HCID 574700773-(5-Nitro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl esterYield 71.1%

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 521585Tris(furan-2-yl)phosphaneCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
80 °C

Procedure

Zn dust (520 mg, 7.95 mmol) was vigorously stirred in THF (2 ml) under nitrogen and 1,2 dibromoethane (84 μl, 0.97 mmol) was added. The suspension was then heated at 80° C. for 8 min and next allowed to cool to room temperature. Trimethylsilyl chloride (115 μl, 0.92 mmol) in THF (1 ml) was then added and the mixture further stirred at room temperature for 45 min. A solution of 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (1.74 g, 6.14 mmol) in THF (2 ml) was then added dropwise to the solution over a period of 15 min and the reaction mixture stirred at room temperature for 2 h. Pd2(dba)3 (90 mg, 0.10 mmol) and P(2-furyl)3 (85 mg, 0.36 mmol) were then added to the mixture, followed by 2-bromo-5-nitropyridine (1.37 g, 6.74 mmol) in THF (4 ml). The mixture was then heated at 55° C. for 3 h, cooled to room temperature and quenched with saturated aqueous NaCl. Extraction with CH2Cl2, drying (Na2SO4) of the organic phase, filtration and evaporation in vacuo provided the crude material, which was purified by flash column chromatography (heptane:ethyl acetate, 3:1) to give the title compound (1.22 g, 71%) as a light yellow oil.

Workup

  1. temperatureto cool to room temperature
  2. stirringthe reaction mixture stirred at room temperature for 2 h
  3. temperatureThe mixture was then heated at 55° C. for 3 h
  4. temperaturecooled to room temperature
  5. customquenched with saturated aqueous NaCl
  6. extractionExtraction with CH2Cl2
  7. customdrying
  8. filtration(Na2SO4) of the organic phase, filtration and evaporation in vacuo
  9. customprovided the crude material, which
  10. customwas purified by flash column chromatography (heptane:ethyl acetate, 3:1)

Sources & evidence

ORD record
ord-b7e8dc73061f401897c890f63878b4f0
Source dataset
uspto-grants-2013_06
Patent number
US08470810B2

Reaction notes

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