Aluminium lithium hydride → 6-Phenylpyridin-3-amine

HRID 1921144Notes

Reaction equation

HRID 1921144 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].CC1N2CCC(/C/1=[N:14]/[C:15]1[CH:16]=[N:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=1)CC2>C1COCC1>[C:21]1([C:18]2[N:17]=[CH:16][C:15]([NH2:14])=[CH:20][CH:19]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1

Participants

4

Reactant 2

HCID 21226445Aluminium lithium hydrideHCID 178429880HCID 178429880, compound

Product 1

HCID 27628776-Phenylpyridin-3-amine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 2-methyl-1-aza-bicyclo[2.2.2]octan-3-one (1.33 g, 9.5 mmol), 6-phenyl-pyridin-3-ylamine (1.25 g, 7.3 mmol) and p-toluene sulfonic acid monohydrate (139 mg, 0.73 mmol) in toluene (40 ml) is heated under reflux for 18 hours using a Dean-Stark apparatus. The toluene is evaporated and the residue is dissolved in ethyl acetate and washed with brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the residual oil purified by silica gel column chromatography (eluent: EtOAc: CH3OH:NH4OH; 9:1:0.1) to afford [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine. A solution of LiAlH4 (1.03 ml, 1 M) in THF is added to a solution of [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine (300 mg, 1.02 mmol) in THF (10 ml). The resulting mixture is stirred at room temperature for 18 hours and then quenched with a saturated aqueous solution of sodium sulfate (1 ml). The solvents are removed by evaporation and the residue is redissolved in ethyl acetate and filtered. The filtrate is evaporated and purified by silica gel column chromatography (eluent: EtOAc: CH3OH: NH4OH; 8.5:1.5:0.1) to afford Rac.-trans-2-Methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-(6-phenyl-pyridin-3-yl)-amine. MS (ES+): m/e=294.4 (MH+); preparative enantiomer separation (column: Chiralpak AD-H 10 um; (4.6×250 mm), eluent: n-hexane : EtOH 50:50, flow: 1.0 ml/min, detector: UV 210 nm): peak 1: 6.29 min; peak 2: 20.16 min.

Workup

  1. customquenched with a saturated aqueous solution of sodium sulfate (1 ml)
  2. customThe solvents are removed by evaporation
  3. dissolutionthe residue is redissolved in ethyl acetate
  4. filtrationfiltered
  5. customThe filtrate is evaporated
  6. custompurified by silica gel column chromatography (eluent: EtOAc: CH3OH: NH4OH; 8.5:1.5:0.1)

Sources & evidence

ORD record
ord-bdb43bf0fb8e4968acbc95557d6e098f
Source dataset
uspto-grants-2012_05
Patent number
US08173667B2

Reaction notes

Loading…