Water → cis-2,6-Dimethyl-4-[3-(2-methyl-3-furanyl)-4-(2-methyl-4-pyridinyl)phenyl]morpholine

HRID 2278451Notes

Reaction equation

HRID 2278451 reaction equation
[CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][C@H:28]([CH3:30])[O:27][C@H:26]([CH3:31])[CH2:25]2)=[CH:20][C:19]=1[C:32]1[CH:36]=[CH:35][O:34][C:33]=1[CH3:37].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C@H:28]1[O:27][C@@H:26]([CH3:31])[CH2:25][N:24]([C:21]2[CH:22]=[CH:23][C:18]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[C:19]([C:32]3[CH:36]=[CH:35][O:34][C:33]=3[CH3:37])[CH:20]=2)[CH2:29]1

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 164142742-Methylpyridine-4-boronic acid pinacol esterHCID 69088074cis-4-[4-Bromo-3-(2-methyl-3-furanyl)phenyl]-2,6-dimethylmorpholine

Product 1

HCID 56971566cis-2,6-Dimethyl-4-[3-(2-methyl-3-furanyl)-4-(2-methyl-4-pyridinyl)phenyl]morpholine

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (313 mg, 1.428 mmol) was added to a solution of cis-4-[4-bromo-3-(2-methyl-3-furanyl)phenyl]-2,6-dimethylmorpholine (500 mg, 1.428 mmol) in a mixture of 1,4-dioxane (6 mL), water (1.000 mL) and sodium carbonate (303 mg, 2.86 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (165 mg, 0.143 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. overnight. Crude LCMS showed starting material and desired product so 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.5 equivalents), tetrakis(triphenylphosphine)palladium(0) (0.05 equivalents) and sodium carbonate (1.0 equivalent) were added and the reaction mixture was stirred and heated at 100° C. in the microwave for a further 1 hour. Crude LCMS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by using a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure. This solid was dissolved in 1:1 MeCN:DMSO (3×0.9 mL) and purified by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (169 mg, 0.443 mmol, 31.0% yield).

Workup

  1. customThe solution was degassed
  2. additionAfter addition

Sources & evidence

ORD record
ord-896cc604f02c47dda5f073b4f537f558
Source dataset
uspto-grants-2015_09
Patent number
US09133178B2

Reaction notes

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