Cesium carbonate → tert-butyl N-(4-fluoropyridin-2-yl)carbamate

HRID 79247

Reaction equation

HRID 79247 reaction equation
Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.[C:9](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:10].C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCCC1>[F:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:9](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonate2×HCID 77922tert-Butyl carbamateHCID 27827922-Chloro-4-fluoropyridine

Product 1

HCID 51354888tert-butyl N-(4-fluoropyridin-2-yl)carbamateYield 70.1%

Reagents, catalysts & solvents 3

HCID 9832798Tris(dibenzylideneacetone) dipalladiumCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a 2 L flask was charged 2-chloro-4-fluoropyridine (20 g, 152 mmol), tert-butyl carbamate (89 g, 760 mmol), tris(dibenzylideneacetone) dipalladium (1.39 g, 1.52 mmol), X-PHOS (2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl) (1.48 g, 3.10 mmol), cesium carbonate (99 g, 588 mmol), and tetrahydrofuran (500 mL) under an atmosphere of dry nitrogen. This mixture was heated at reflux under nitrogen for 7 hours. A further 1 equivalent of cesium carbonate was added to drive the reaction to completion (heated a further 7 hours). The mixture was cooled to ambient temperature, filtered through Celite and washed with ethyl acetate. The filtrate was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate twice. The combined organic phases were washed with brine and dried with sodium sulfate, concentrated under vacuum, and purified by column chromatography to give tert-butyl 4-fluoropyridin-2-ylcarbamate as a pale yellow solid (22.6 g).

Workup

  1. temperatureThis mixture was heated
  2. temperatureat reflux under nitrogen for 7 hours
  3. customthe reaction to completion (
  4. temperatureheated a further 7 hours)
  5. filtrationfiltered through Celite
  6. washwashed with ethyl acetate
  7. customThe filtrate was partitioned between saturated sodium bicarbonate and ethyl acetate
  8. extractionThe aqueous phase was extracted with ethyl acetate twice
  9. washThe combined organic phases were washed with brine
  10. dry with materialdried with sodium sulfate
  11. concentrationconcentrated under vacuum
  12. custompurified by column chromatography

Sources & evidence

ORD record
ord-49adccde2ee24f8e8aa65af08f469fc0
Source dataset
uspto-grants-2014_09
Patent number
US08841455B2

Linked notes

Loading…