Citric Acid → N-(5-bromo-2-chloro-3-pyridinyl)methanesulfonamide

HRID 241041Notes

Reaction equation

HRID 241041 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])[C:5]([Cl:8])=[N:6][CH:7]=1

Participants

8

Reactant 5

HCID 311Citric AcidHCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 218583543-Amino-5-bromo-2-chloropyridine

Product 1

HCID 59519513N-(5-bromo-2-chloro-3-pyridinyl)methanesulfonamideYield 38%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 5-bromo-2-chloropyridin-3-amine (1.0 g, 4.8 mmol) and diisopropylethylamine (1.85 mL, 10.6 mmol) in dichloromethane (25 mL) was cooled to 0° C., and then methanesulfonyl chloride (750 uL, 9.6 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 15 min and was then warmed to rt. After stirring for 2 h, water was added, and then the biphasic mixture was partitioned. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was then dissolved in dioxane (10 mL) and water (10 mL). Potassium carbonate (2.76 g, 20 mmol) was added, and the reaction mixture was stirred for 15 h at rt. Water was then added to the mixture which was subsequently acidified with aqueous citric acid (10%). The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (gradient, 100% hexanes to 50% hexanes:50% ethyl acetate) to provide N-(5-bromo-2-chloropyridin-3-yl)methanesulfonamide (520 mg, 1.82 mmol, 38% yield) as a light pink solid. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, 1H), 8.14 (d, 1H), 6.83 (br s, 1H), 3.11 (s, 3H); MS (EI) for C6H6BrClN2O2S: 285, 287, 289 (Br+Cl isotopes, MH+).

Workup

  1. temperaturewas then warmed to rt
  2. stirringAfter stirring for 2 h
  3. customthe biphasic mixture was partitioned
  4. dry with materialThe organic phase was dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. dissolutionThe residue was then dissolved in dioxane (10 mL)
  8. stirringthe reaction mixture was stirred for 15 h at rt
  9. extractionThe aqueous mixture was extracted twice with ethyl acetate
  10. dry with materialThe combined organic extracts were dried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe residue was purified by flash chromatography (gradient, 100% hexanes to 50% hexanes:50% ethyl acetate)

Sources & evidence

ORD record
ord-36f2964eba1a419f8416cd5f1c48d913
Source dataset
uspto-grants-2014_02
Patent number
US08648066B2

Reaction notes

Loading…