2-Fluoro-3-iodopyrazine → Tert-butyl 3-(3-fluoropyrazin-2-yl)pyrrolidine-1-carboxylate

HRID 473726Notes

Reaction equation

HRID 473726 reaction equation
[F:1][C:2]1[C:7](I)=[N:6][CH:5]=[CH:4][N:3]=1.[I-].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([Zn+])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu]I.CC(N(C)C)=O>[F:1][C:2]1[C:7]([CH:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:21]2)=[N:6][CH:5]=[CH:4][N:3]=1

Participants

6

Reactant 2

HCID 153696932-Fluoro-3-iodopyrazineHCID 178452042HCID 178452042, compound

Product 1

HCID 59374164Tert-butyl 3-(3-fluoropyrazin-2-yl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
80 °C

Procedure

Into an oven-dried flask were charged 2-fluoro-3-iodopyrazine (3.08 g, 13.8 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(ii)complex with dichloramethane (0.34 g, 0.41 mmol), copper(i) iodide (0.16 g, 0.83 mmol), and DMA (20 mL). The resulting mixture was degassed with alternating vacuum/nitrogen purges. The (1-(tert-butoxycarbonyl)pyrrolidin-3-yl)zinc(II) iodide (6.98 g, 19.3 mmol) solution from previous step was filtered through a regular filter into the mixture. It was degassed one more time and then heated to 80° C. with stirring for 16 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and 1 N NH4Cl. The aqueous layer was back extracted with EtOAc (2×) and the combined EtOAc layers were washed once again with 1 N NH4Cl, then with brine, dried (Na2SO4) and concentrated. The crude material as chromatographed through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide tert-butyl 3-(3-fluoropyrazin-2-yl)pyrrolidine-1-carboxylate as orange oil. MS (ESI, pos. ion) m/z: 212.0 (M−56).

Workup

  1. customThe resulting mixture was degassed
  2. filtrationa regular filter into the mixture
  3. customIt was degassed one more time
  4. temperatureAfter cooling to RT
  5. customthe reaction mixture was partitioned between EtOAc and 1 N NH4Cl
  6. extractionThe aqueous layer was back extracted with EtOAc (2×)
  7. washthe combined EtOAc layers were washed once again with 1 N NH4Cl
  8. dry with materialwith brine, dried (Na2SO4)
  9. concentrationconcentrated
  10. customThe crude material as chromatographed through a Redi-Sep pre-packed silica gel column (120 g)
  11. washeluting with a gradient of 0% to 30% EtOAc in hexane

Sources & evidence

ORD record
ord-b1674c970c814cf68fc09a207b013f51
Source dataset
uspto-grants-2014_01
Patent number
US08637500B2

Reaction notes

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