Lithium Hexamethyldisilazide → 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

HRID 1619635Notes

Reaction equation

HRID 1619635 reaction equation
[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28]([C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]>O1CCCC1.C(OCC)(=O)C>[C:28]([C:30]1[CH:31]=[C:32]([S:37]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]

Participants

6

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 27789083-Cyano-4-fluorobenzenesulfonyl chlorideHCID 57732216N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine

Product 1

HCID 580422543-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamideYield 71%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

N-(2,4-Dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 42.8 g, 170 mmol) was dissolved in anhydrous tetrahydrofuran (600 mL) and stirred under a nitrogen atmosphere at −78° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (238 mL, 238 mmol) was added drop wise over 30 minutes maintaining the temperature between −65° C. and −70° C. The reaction mixture was left at −78° C. for 5 minutes, then allowed to warm to −10° C. over 1.5 hours. Upon reaching −10° C., the brown reaction mixture was cooled to −78° C. again, and a solution of 3-cyano-4-fluorobenzene sulfonyl chloride (48.6 g, 221 mmol) in tetrahydrofuran (200 mL) was added drop wise over 30 minutes maintaining the temperature between −65° C. and −70° C. The brown solution was allowed to warm gradually to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, and extracted with further ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown residue. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (52.3 g, 71%).

Workup

  1. temperaturemaintaining the temperature between −65° C. and −70° C
  2. temperatureto warm to −10° C. over 1.5 hours
  3. customUpon reaching −10° C.
  4. temperaturethe brown reaction mixture was cooled to −78° C. again
  5. temperaturemaintaining the temperature between −65° C. and −70° C
  6. temperatureto warm gradually to ambient temperature
  7. stirringstirred for 18 hours
  8. washwashed with a saturated ammonium chloride solution
  9. extractionextracted with further ethyl acetate
  10. dry with materialThe combined organics were dried over anhydrous magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customto afford a brown residue
  14. customThe residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution)

Sources & evidence

ORD record
ord-01415a19654e4844acca57344859c620
Source dataset
uspto-grants-2014_07
Patent number
US08772293B2

Reaction notes

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