Piperidin-4-ol → 2'-(4-Methoxybenzyloxy)-4'-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-4-ol

HRID 632829Notes

Reaction equation

HRID 632829 reaction equation
Br[C:2]1[C:3]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:3]2[C:2]([N:23]3[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]3)=[C:7]([CH3:8])[CH:6]=[CH:5][N:4]=2)=[CH:12][CH:13]=1

Participants

7

Reactant 4

HCID 79341Piperidin-4-olHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 670001042-(4-Methoxybenzyloxy)-3-bromo-4-methylpyridine

Product 1

HCID 1212495502'-(4-Methoxybenzyloxy)-4'-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-4-ol

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

A mixture of 3-bromo-2-(4-methoxybenzyloxy)-4-methylpyridine (6.40 g, 20.77 mmol), 4-hydroxypiperidine (3.15 g, 31.15 mmol), tris(dibenzylideneacetone)dipalladium (761 mg, 0.831 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.03 g, 1.66 mmol), and sodium-t-butoxide (2.79 g, 29.08 mmol) in anhydrous toluene (200 ml) was heated at reflux under nitrogen for 22 hours. Upon cooling to room temperature, the reaction mixture was filtered through celite and the filtrate was diluted with ethyl acetate, washed with sat'd NaCl(aq.), dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes: EtOAc) gave the title compound as a black, viscous oil (4.76 g, 70%).

Workup

  1. temperaturewas heated
  2. temperatureat reflux under nitrogen for 22 hours
  3. filtrationthe reaction mixture was filtered through celite
  4. additionthe filtrate was diluted with ethyl acetate
  5. washwashed with sat'd NaCl(aq.)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. washElution through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes: EtOAc)

Sources & evidence

ORD record
ord-3a82ce8dbb0b443e8eb0d13131ec68a3
Source dataset
uspto-grants-2016_04
Patent number
US09321766B1

Reaction notes

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