2-Fluoro-3-iodopyrazine → Tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate

HRID 887468Notes

Reaction equation

HRID 887468 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[CH2:22][CH2:21][CH:20]([Zn+])[CH2:19][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[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]2)=[N:6][CH:5]=[CH:4][N:3]=1

Participants

6

Reactant 2

HCID 153696932-Fluoro-3-iodopyrazineHCID 178452044HCID 178452044, compound

Product 1

HCID 59351396Tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-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

In an oven-dried flask were charged 2-fluoro-3-iodopyrazine (0.829 g, 3.70 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(ii) complex with dichloramethane (0.091 g, 0.111 mmol), copper(i) iodide (0.042 g, 0.222 mmol), and DMA (3 mL). The resulting mixture was degassed with alternating vacuum/nitrogen purges. The (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (1.951 g, 5.18 mmol) solution from previous step was filtered 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 treated with methyl bert-butylether (13 ml) and 1 N NH4Cl (13 ml). The organic layer was partitioned between EtOAc and 1 N NH4Cl and the aqueous layer was back extracted with EtOAc (2×). The combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude material was chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate as orange oil. MS (ESI, pos. ion) m/z: 226.0 (M-56).

Workup

  1. customThe resulting mixture was degassed
  2. customIt was degassed one more time
  3. temperatureAfter cooling to RT
  4. additionthe reaction mixture was treated with methyl bert-butylether (13 ml) and 1 N NH4Cl (13 ml)
  5. customThe organic layer was partitioned between EtOAc and 1 N NH4Cl
  6. extractionthe aqueous layer was back extracted with EtOAc (2×)
  7. washThe combined organic layer was washed with water, brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. washeluting with a gradient of 0% to 20% EtOAc in hexane

Sources & evidence

ORD record
ord-996ca1d943cf4e6dbbb3cfefa8274003
Source dataset
uspto-grants-2012_08
Patent number
US08247418B2

Reaction notes

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