Sulfuric Acid → 5-Bromo-2-chloro-4-ethoxypyridine

HRID 1050006Notes

Reaction equation

HRID 1050006 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.OS(O)(=O)=O.[Br:16]N1C(=O)CCC1=O>CC(=O)OCC>[Br:16][C:5]1[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1

Participants

5

Reactant 3

HCID 1118Sulfuric AcidHCID 67184N-bromobutanimideHCID 8172382-Chloro-4-ethoxypyridine

Product 1

HCID 707008775-Bromo-2-chloro-4-ethoxypyridineYield 41.3%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

2-Chloro-4-ethoxypyridine (100 g, 0.63 mol) was added to H2SO4 (500 mL) slowly. Then 1-bromopyrrolidine-2,5-dione (124.2 g, 0.70 mol) was added into above mixture at rt. The mixture was stirred at 80° C. for 3 h. TLC (PE/EA=10:1, Rf=0.5) showed the reaction was finished. The reaction mixture was poured into ice-water (2 L), and extracted with EA (1 L×3). The organic layer was washed with saturated Na2CO3 solution (1 L×2), dried over Na2SO4 and concentrated. The residue was purified by silica column chromatography (PE/EA=60:1-30:1). All fractions found to contain product by TLC (PE/EA=10:1, Rf=0.5) were combined and concentrated to yield 5-bromo-2-chloro-4-ethoxypyridine (60.9 g, 0.26 mol, 40% yield): 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.14 (s, 1H), 4.32-4.10 (m, 2H), 1.58-1.35 (m, 3H); ES-LCMS m/z 237 (M+2).

Workup

  1. extractionextracted with EA (1 L×3)
  2. washThe organic layer was washed with saturated Na2CO3 solution (1 L×2)
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customThe residue was purified by silica column chromatography (PE/EA=60:1-30:1)
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-08a008afa0544c88976f0caefddc4839
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

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