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

HRID 1666449Notes

Reaction equation

HRID 1666449 reaction equation
[CH3:1][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]>[CH3:1][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 668754484-Methyl-3-(5-(trifluoromethyl)pyridin-2-yloxy)phenylboronic acid

Product 1

HCID 66876250tert-Butyl 4-(4-methyl-3-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylateYield 29.3%

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-methyl-3-(5-(trifluoromethyl)pyridin-2-yloxy)phenylboronic acid (1.13 g, 0.0038 mol) and tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (871 mg, 0.006 mol) in THF (10.5 mL) was added K3PO4 (2.43 g, 0.011 mol). The flask was put under vacuum and flushed with N2 three times. Water (0.19 mL) was added and the system was flushed with N2 again. PdCl2(dppf) (310 mg, 0.0004 mol) 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 (0.50 g). 1H NMR (500 MHz, CDCl3): δ 8.42 (s, 1H), 7.90 (dd, J=2.25 Hz, J=8.75 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.03-6.98 (m, 2H), 6.89 (s, 1H), 6.31 (s, 1H), 3.49 (t, J=5.0 Hz, 2H), 3.40 (t, J=5.5 Hz, 2H), 2.47 (t, J=5 Hz, 2H), 2.30 (s, 3H), 2.13 (s, 3H), 1.46 (s, 9H).

Workup

  1. customflushed with N2 three times
  2. additionWater (0.19 mL) was added
  3. customthe system was flushed with N2 again
  4. customthe system was flushed with N2 two to three times again
  5. concentrationThe reaction mixture was concentrated
  6. additiondiluted with water
  7. extractionextracted with EtOAc
  8. extractionThe organic extract
  9. washwas washed with brine
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified by column chromatography (2.5% EtOAc-97.5% Hexane)

Sources & evidence

ORD record
ord-1723cdef61ec4135ae472207751c3f93
Source dataset
uspto-grants-2011_10
Patent number
US08044052B2

Reaction notes

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