2-Bromopyridine → N-[(4-{4-[(1-isopropyl piperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridin-2-amine

HRID 272966Notes

Reaction equation

HRID 272966 reaction equation
[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=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]>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 79732-BromopyridineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 68576458(4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine

Product 1

HCID 59837502N-[(4-{4-[(1-isopropyl piperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridin-2-amineYield 26.4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

(4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (300 mg, 0.9 mmol), 2-bromopyridine (50 μL, 0.75 mmol), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.018 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.036 mmol) and sodium tert-butoxide (100 mg, 1 mmol) were heated at 70° C. in toluene (6 ml) for 24 hours under nitrogen. The reaction was partitioned between aqueous sodium bicarbonate (302 ml) and dichloromethane (2×75 ml). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4, to 94:6:0.6 by volume) to provide the title compound (81 mg, 22%) as a white solid after trituration in diethyl ether. 1H NMR (400 MHz, CDCl3) δ 1.11 (d, 6H), 1.86-1.95 (m, 4H), 2.07-2.16 (m, 4H), 2.46-2.51 (m, 2H), 2.82-2.86 (m, 3H), 3.49 (d, 2H), 3.56-3.61 (m, 2H), 3.80-3.85 (m, 2H), 4.03 (m, 1H), 4.33 (m, 1H), 6.22 (d, 1H), 6.51 (t, 1H), 6.91 (d, 2H), 7.24 (d, 2H), 7.32 (t, 1H), 8.01 (d, 1H). HRMS ESI+ m/z 410.2793 [MH]+.

Workup

  1. customThe reaction was partitioned between aqueous sodium bicarbonate (302 ml) and dichloromethane (2×75 ml)
  2. dry with materialdried over sodium sulphate
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4, to 94:6:0.6 by volume)

Sources & evidence

ORD record
ord-a24f8d3ad8a04d82a12cab144db879af
Source dataset
uspto-grants-2008_11
Patent number
US07456164B2

Reaction notes

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