Substitued Aza-Oxindole Derivatives

Harris etal, US Patent 6,624,171 (September 23, 2003) Assignee SmithKline Beecham Corporation 

Utility Agent for Reducing Epithelial Cytotoxicity Induced During 

At ambient temperature 3,3-dibromo-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (13.4 mmol) was dissolved in 100 ml apiece t-butyl alcohol and water followed by the dropwise addition of bromine (34.3 mmol) over 20 minutes. Thereafter 15 ml NaHC03 was added over 30 minutes to raise the pH to 6.5. A yellow solid formed and was removed. The filtrate was reduced to 100 ml, extracted twice with 50 ml chloroform, dried, concentrated, and the product isolated in 98% yield. H-NMR data supplied. 

The product from Step 1 (13.4 mmol) was dissolved in 100 ml apiece THE and a saturated solution of NH4CI, placed in a water bath, and activated zinc dust (230 mmol) added. The mixture stirred 20 minutes and was then filtered through a pad of diatomaceous earth. The organic layer was separated and the aqueous layer extracted with 20 ml THF. The organic phase was washed with brine, dried, and concentrated. The residue was triturated with 20 ml water and the product isolated in 71% yield as a tan solid. NMR data supplied. 

The product from Step 2 (3.52mmol), 2-tributyltinfuran (3.52 mmol), and NEt4Cl H2O (10.6 mmol) were dissolved in 10 ml acetonitrile, bistriphenylphosphine dichloropalla-dium (II) (0.35 mmol) added, and the reaction mixture heated to 85 °C 16 hours. Thereafter, it was cooled to ambient temperature, 60 ml 10% aqueous KF added, the mixture stirred 20 minutes, and 60 ml EtOAc added. The solution was passed through celite, the layers separated, volatiles removed, and the residue triturated with diethyl ether. The product was isolated as a light yellow solid in 36% yield. NMR data supplied. 

---