N,N,N',N'-Tetramethylethylenediamine → Tert-butyl 2-(2-fluoropyridin-3-yl)piperidine-1-carboxylate

HRID 1880148Notes

Reaction equation

HRID 1880148 reaction equation
[N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(CCN(C)C)C.C([Li])(CC)C.C1CCCCC1.[F:33][C:34]1[C:39](I)=[CH:38][CH:37]=[CH:36][N:35]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[NH4+].[OH-]>[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[F:33][C:34]1[C:39]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:38][CH:37]=[CH:36][N:35]=1

Participants

11

Reactant 7

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 8078CyclohexaneHCID 14923Ammonium HydroxideHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 70095012-Fluoro-3-iodopyridineHCID 7010304N-(tert-butoxycarbonyl)piperidineHCID 178418400CID 53628100

Product 1

HCID 59327149Tert-butyl 2-(2-fluoropyridin-3-yl)piperidine-1-carboxylateYield 4.8%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 3007855ZincchlorideCatalystHCID 3283Diethyl EtherSolvent3×

Procedure

To a −78° C. solution of tert-butyl piperidine-1-carboxylate (1.0 mL, 5.20 mmol), dry ether (20 mL) and TMEDA (0.82 mL, 5.47 mmol) was added sec-butyllithium, 1.4M in cyclohexane (3.90 mL, 5.46 mmol) dropwise over 5 minutes. After 2 hours, a solution of zinc chloride, 0.5M in ether (6.8 mL, 6.80 mmol) was added over 7 minutes. After 30 minutes, the mixture was warmed to ambient temperature and stirred for a further 30 minutes then 2-fluoro-3-iodopyridine (1511 mg, 6.78 mmol), palladium(ii) acetate (127 mg, 0.566 mmol), tri-t-butylphosphonium tetrafluoroborate (268 mg, 0.924 mmol) was added in one portion. After 18 hours, NH4OH (10 mL, 10% aqueous solution) was added dropwise, followed by Et2O (10 mL). The organic layer was extracted, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 0% to 40% EtOAc in hexane, to provide tert-butyl 2-(2-fluoropyridin-3-yl)piperidine-1-carboxylate (70 mg, 0.250 mmol) as a colorless oil. [M+Na]=303.2.

Workup

  1. waitAfter 30 minutes
  2. waitAfter 18 hours
  3. extractionThe organic layer was extracted
  4. washwashed with brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customchromatographed through a Redi-Sep® pre-packed silica gel column (40 g)
  8. washeluting with 0% to 40% EtOAc in hexane

Sources & evidence

ORD record
ord-fc3d12de16b341c3931ce28bc7fa1d28
Source dataset
uspto-grants-2012_11
Patent number
US08318718B2

Reaction notes

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