5-Bromopyrimidine → 1'-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]

HRID 967938Notes

Reaction equation

HRID 967938 reaction equation
[NH:1]1[CH2:5][CH2:4][C:3]2([CH2:10][CH:9]3[CH2:11][N:6]2[CH2:7][CH2:8]3)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].Br[C:65]1[CH:66]=[N:67][CH:68]=[N:69][CH:70]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:67]1[CH:66]=[C:65]([N:1]2[CH2:5][CH2:4][C:3]3([CH2:10][CH:9]4[CH2:11][N:6]3[CH2:7][CH2:8]4)[CH2:2]2)[CH:70]=[N:69][CH:68]=1

Participants

7

Reactant 4

HCID 783445-BromopyrimidineHCID 634876Binap, (A+-)-HCID 22291224Spiro[1-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]HCID 23665647Potassium tert-butoxide

Product 1

HCID 103989741'-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]Yield 354.6%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
125 °C

Procedure

A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (100 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.0018 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (24 mg, 0.0036 mmol), potassium tert-butoxide (300 mg, 2.6 mmol), and 5-bromopyrimidine (114 mg, 0.7 mmol) in dry toluene (10 mL) was placed in a sealed tube under argon and heated at 125° C. for 17 h. The reaction was cooled to 0° C. and the contents transferred to a 100 mL round bottom flask. The solvent was removed by rotary evaporation and the residue was dissolved in a saturated solution of NaHCO3 (10 mL) and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to give a dark colored syrup. This was purified by column chromatography, using MeOH:CHCl3:NH4OH (8:2:0.01, v/v) as the eluent, to afford 49.0 mg of 1′-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (32%) as a viscous brown oil.

Workup

  1. customwas placed in a sealed tube under argon
  2. temperatureThe reaction was cooled to 0° C.
  3. customthe contents transferred to a 100 mL round bottom flask
  4. customThe solvent was removed by rotary evaporation
  5. dissolutionthe residue was dissolved in a saturated solution of NaHCO3 (10 mL)
  6. extractionextracted with chloroform (4×15 mL)
  7. dry with materialThe combined chloroform extracts were dried (K2CO3)
  8. filtrationfiltered
  9. concentrationconcentrated by rotary evaporation
  10. customto give a dark colored syrup
  11. customThis was purified by column chromatography

Sources & evidence

ORD record
ord-5f8594de7d4a4462bf81d80429302770
Source dataset
uspto-grants-2005_10
Patent number
US06956042B2

Reaction notes

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