Acetic Anhydride → Acetic acid 3-phenylsulfanyl-pyridin-2-ylmethyl ester

HRID 250973Notes

Reaction equation

HRID 250973 reaction equation
[H-].[Na+].C1(S)C=CC=CC=1.BrC1C(C)=[N+]([O-])C=CC=1.[CH3:19][C:20]1[C:25]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:23]=[CH:22][N+:21]=1[O-].[CH3:34][C:35]([O:37]C(C)=O)=[O:36]>CN(C=O)C.C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[C:27]1([S:26][C:25]2[C:20]([CH2:19][O:37][C:35](=[O:36])[CH3:34])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1

Participants

10

Reactant 5

HCID 7918Acetic AnhydrideHCID 7969ThiophenolHCID 24758Sodium hydrideHCID 144029523-Bromo-2-methylpyridine N-oxideHCID 672725392-Methyl-3-phenylsulfanyl-pyridine 1-oxide

Product 1

HCID 67273029Acetic acid 3-phenylsulfanyl-pyridin-2-ylmethyl esterYield 25%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of 60% NaH (577 mg, 14.4 mmol) in DMF (15 mL) at 0° C. was added thiophenol (1.47 mL, 14.4 mmol) and the resultant mixture was warmed to room temperature and stirred for 1.5 h. To this mixture was added the 3-Bromo-2-methyl-pyridine 1-oxide (900 mg, 4.79 mmol) and the resultant yellow solution was heated to 80° C. for 96 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with EtOAc (100 mL), washed with brine (4×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (EtOAc/MeOH, 100:0 then 95:5) gave a mixture of 2-methyl-3-phenylsulfanyl-pyridine 1-oxide and a di-substituted thiophenol by-product. The mixture was treated with Ac2O (3 mL) and heated at 80° C. overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 (40 mL), H2O (10 mL) and saturated aqueous NaHCO3 (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30) gave Acetic acid 3-phenylsulfanyl-pyridin-2-ylmethyl ester (259 mg, 25% over 2 steps) as a yellow oil. 1H NMR (CDCl3) δ 2.11 (s, 3H), 5.37 (s, 2H), 7.18 (dd, 1H, J=7.9, 4.9 Hz), 7.27-7.38 (m, 5H), 7.53 (dd, 1H, J=7.9, 1.7 Hz), 8.50 (dd, 1H, J=4.7, 1.8 Hz).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated under reduced pressure
  3. additionThe residue was treated with EtOAc (100 mL)
  4. washwashed with brine (4×50 mL)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customPurification by flash chromatography on silica gel (EtOAc/MeOH, 100:0
  9. custom95:5) gave
  10. temperatureheated at 80° C. overnight
  11. temperatureThe mixture was cooled to room temperature
  12. customThe aqueous phase was separated
  13. extractionextracted with CH2Cl2 (2×20 mL)
  14. dry with materialThe combined organic extracts were dried (Na2SO4)
  15. filtrationfiltered
  16. concentrationconcentrated
  17. customPurification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30)

Sources & evidence

ORD record
ord-a41bf9f6da16471dbfe376a6e4ad930f
Source dataset
uspto-grants-2011_01
Patent number
US07863293B2

Reaction notes

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