Potassium Phosphate, Tribasic → tert-Butyl 4-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate

HRID 1666443Notes

Reaction equation

HRID 1666443 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.Br[CH:23]=[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:23]=[C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 45489892tert-Butyl 4-(bromomethylidene)piperidine-1-carboxylateHCID 668759444-Chloro-3-(5-(trifluoromethyl)pyridin-2-yloxy)phenylboronic acid

Product 1

HCID 66875839tert-Butyl 4-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylateYield 8.2%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 4-chloro-3-(5-(trifluoromethyl)pyridin-2-yloxy)phenylboronic acid (2.8 g, 8.82 mmol) and tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (2.02 g, 7.32 mmol) in THF (10 mL) was added K3PO4 (4.7 g, 26.63 mmol). The air inside the flask was removed under vacuum and flushed with N2 three times. Water (0.56 mL) was added and the system was flushed with N2 again. PdCl2(dppf) (720.3 mg, 0.882 mmol) was added and the system was flushed with N2 two to three times again. The reaction mixture was refluxed at 50° C. for 1 h. The reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (2.5% EtOAc-97.5% Hexane) to give the pure title compound (280 mg). 1H NMR (500 MHz, CDCl3): δ 8.43 (s, 1H), 7.97 (d, J=8.65 Hz, 1H), 7.70 (d, J=1.9 Hz, 1H), 7.55 (d, J=8.35 Hz, 1H), 7.32 (d, J=8.35 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 5.99 (s, 1H), 3.44 (m, 4H), 2.39 (m, 2H), 2.24 (m, 2H), 1.47 (s, 9H).

Workup

  1. customThe air inside the flask was removed under vacuum
  2. customflushed with N2 three times
  3. additionWater (0.56 mL) was added
  4. customthe system was flushed with N2 again
  5. customthe system was flushed with N2 two to three times again
  6. concentrationThe reaction mixture was concentrated
  7. additiondiluted with water
  8. extractionextracted with EtOAc
  9. extractionThe organic extract
  10. washwas washed with brine
  11. dry with materialdried over Na2SO4
  12. concentrationconcentrated under reduced pressure
  13. customThe residue was purified by column chromatography (2.5% EtOAc-97.5% Hexane)

Sources & evidence

ORD record
ord-b361ccd816b34287b6dc9c44aa932405
Source dataset
uspto-grants-2011_10
Patent number
US08044052B2

Reaction notes

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