tert-Butyl bromoacetate → (6-Cyano-2-methyl-indolizin-3-yl)-acetic acid tert-butyl ester

HRID 402885

Reaction equation

HRID 402885 reaction equation
Br[C:2]1[N:10]2[C:5]([CH:6]=[CH:7][C:8]([C:11]#[N:12])=[CH:9]2)=[CH:4][C:3]=1[CH3:13].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>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].CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[C:19]([O:18][C:16](=[O:17])[CH2:15][C:2]1[N:10]2[C:5]([CH:6]=[CH:7][C:8]([C:11]#[N:12])=[CH:9]2)=[CH:4][C:3]=1[CH3:13])([CH3:22])([CH3:21])[CH3:20]

Participants

5

Reactant 2

HCID 79177tert-Butyl bromoacetateHCID 591920153-Bromo-2-methylindolizine-6-carbonitrile

Product 1

HCID 68708411(6-Cyano-2-methyl-indolizin-3-yl)-acetic acid tert-butyl esterYield 68.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 12024214Ditert-butyl(cyclopenta-1,3-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzeneCatalyst

Procedure

Under an atmosphere of argon, 3-bromo-2-methyl-indolizine-6-carbonitrile (500 mg, 2.12 mmol), Pd2(dba)3 (19.5 mg, 21.2 μmol, 0.01 equiv), 1,2,3,4,5-pentaphenyl-1-(di-tert-butylphosphino)ferrocene (15.1 mg, 21.2 μmol, 0.01 equiv) and the isolated, recrystallized Reformatsky reagent prepared from tert-butyl bromoacetate (609 mg, 2.33 mmol, 1.1 equiv) are placed in a 50-ml round bottom flask. After three careful degassing cycles, anhydrous THF (8 ml) is added, and the reaction mixture is stirred at room temperature. After 1 hour at room temperature, TLC analysis indicated incomplete conversion. Consequently, additional portions of the palladium salt, the phosphino ligand and the Reformatsky reagent are added (same quantities as above). After 1 additional hour, reagents are added again, to achieve complete conversion after a total reaction time of 4 hours at room temperature. The reaction mixture is diluted with water, and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (hexane/EtOAc 6:1) affords the title compound (390 mg, 68%). 1H NMR (400 MHz, CDCl3): δ=8.22 (t, J=1.2 Hz, 1H), 7.36 (d, J=9.2 Hz, 1H), 7.21 (s, 1H), 6.67 (dd, J=9.3/1.5 Hz, 1H). 3.61 (s, 2H), 2.31 (s, 3H), 1.44 (s, 9H). MS (ES+): 271 (M+H)+.

Workup

  1. customare placed in a 50-ml round bottom flask
  2. customAfter three careful degassing cycles, anhydrous THF (8 ml)
  3. additionis added
  4. additionConsequently, additional portions of the palladium salt, the phosphino ligand and the Reformatsky reagent are added (same quantities as above)
  5. additionAfter 1 additional hour, reagents are added again
  6. customafter a total reaction time of 4 hours
  7. customat room temperature
  8. additionThe reaction mixture is diluted with water
  9. extractionextracted three times with EtOAc
  10. washThe combined organic layers are washed with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customPurification of the residue via flash chromatography (hexane/EtOAc 6:1)

Sources & evidence

ORD record
ord-bf90f351617d448b8f04aa8cf9076f69
Source dataset
uspto-grants-2014_06
Patent number
US08742132B2

Linked notes

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