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

HRID 473696Notes

Reaction equation

HRID 473696 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 tert-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 x). The combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude material was chromatographed 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 tert-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 x)
  7. washThe combined organic layer was washed with water, brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. customThe crude material was chromatographed through a Redi-Sep pre-packed silica gel column (40 g)
  11. washeluting with a gradient of 0% to 20% EtOAc in hexane

Sources & evidence

ORD record
ord-1a7e6978e35640858955ff95332a8f15
Source dataset
uspto-grants-2014_01
Patent number
US08637500B2

Reaction notes

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