Cesium carbonate → 5-(3-Methylazetidin-1-yl)-2-nitropyridine

HRID 1919035Notes

Reaction equation

HRID 1919035 reaction equation
C1(S([O-])(=O)=O)C=CC=CC=1.[CH3:11][CH:12]1[CH2:15][NH2+:14][CH2:13]1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(Cl)Cl.CO.O.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].O1CCOCC1>[CH3:11][CH:12]1[CH2:15][N:14]([C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[N:20][CH:21]=2)[CH2:13]1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 8176205-Bromo-2-nitropyridineHCID 866612493-Methylazetidinium benzenesulfonate

Product 1

HCID 580441445-(3-Methylazetidin-1-yl)-2-nitropyridineYield 69%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 3-methylazetidinium benzenesulfonate (4.02 g, 17.5 mmol), 2-nitro-5-bromo pyridine (3.56 g, 17.5 mmol), cesium carbonate (28.5 g, 87.7 mmol) and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (862 mg, 1.50 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (800 mg, 0.900 mmol) were added. A reflux condenser was attached to the flask, and the reaction mixture was heated at reflux for 3 h. After this time, the mixture was cooled to room temperature and diluted with 90:10 methylene chloride/methanol (100 mL) and water (75 mL), and the layers were separated. The aqueous layer was extracted with 90:10 methylene chloride/methanol (2×50 mL), and the combined organic extracts were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 0% to 80% ethyl acetate/hexanes) to afford 236a in 69% yield (2.35 g) as an amorphous yellow solid: mp 141-143° C.; 1H NMR (500 MHz, CDCl3) d 8.12 (d, 1H, J=9.0 Hz), 7.60 (d, 1H, J=2.5 Hz), 6.66 (dd, 1H, J=9.0, 2.5 Hz), 4.23 (t, 2H, J=8.5 Hz), 3.68 (m, 2H), 2.99 (m, 1H), 1.36 (d, 3H, J=7.0 Hz; MS (ESI+) m/z 194.0 (M+H)

Workup

  1. customA 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet
  2. customAfter bubbling nitrogen through the resulting suspension for 30 min
  3. customA reflux condenser was attached to the flask
  4. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 3 h
  6. customthe layers were separated
  7. extractionThe aqueous layer was extracted with 90:10 methylene chloride/methanol (2×50 mL)
  8. washthe combined organic extracts were washed with brine
  9. dry with materialdried over sodium sulfate
  10. customThe drying agent was removed by filtration
  11. concentrationThe filtrate was concentrated under reduced pressure
  12. customthe resulting residue was purified by flash column chromatography (silica, 0% to 80% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-65236d20153a45e48f7e3d51f05ed397
Source dataset
uspto-grants-2013_12
Patent number
US08618107B2

Reaction notes

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