18-Crown-6 → tert-Butyl 4-(3-chloro-4-cyanoisothiazol-5-yl)phenylcarbamate

HRID 871001Notes

Reaction equation

HRID 871001 reaction equation
[Cl:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Cl)[S:4][N:3]=1.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[CH:23][CH:22]=2)[S:4][N:3]=1

Participants

9

Reactant 4

HCID 2855718-Crown-6HCID 305706Dichloro-1,2-thiazole-4-carbonitrileHCID 522689Potassium FluorideHCID 3613184(4-Boc-Aminophenyl)Boronic Acid

Product 1

HCID 86689222tert-Butyl 4-(3-chloro-4-cyanoisothiazol-5-yl)phenylcarbamateYield 85%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 3,5-dichloroisothiazole-4-carbonitrile (5.37 g, 30 mmol), 4-(tertbutoxycarbonylamino)phenylboronic acid (14.22 g, 60 mmol), potassium fluoride (6.11 g, 105 mmol), 18-crown-6 (3.96 g, 15 mmol), and palladium acetate (337 mg, 1.5 mmol) in toluene (250 ml) was heated at reflux for 6 hours. The reaction was cooled to RT and the mixture was diluted with water and EtOAc. Layers were separated and the aqueous layer was extracted with EtOAc×3. The combined organics was washed with brine and dried with MgSO4, filtered, and concentrated. The crude product was purified by flash silica gel column eluted with 5-15% EtOAc in hexanes to obtain the above compound as a white crystalline solid (8.55 g, 85%). NMR and MS spectra are consistent with the structure. HPLC purity 97.6%.

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 6 hours
  3. customLayers were separated
  4. extractionthe aqueous layer was extracted with EtOAc×3
  5. washThe combined organics was washed with brine
  6. dry with materialdried with MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified by flash silica gel column
  10. washeluted with 5-15% EtOAc in hexanes

Sources & evidence

ORD record
ord-5d4d83079fd54ad1bf1c1032eb1124ce
Source dataset
uspto-grants-2015_03
Patent number
US08969583B2

Reaction notes

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