A Traceless Approach for the Solid-Phase Parallel Synthesis of Trisubstituted Oxindoles

摘要

Solid-phase organic synthesis is a powerful tool for the preparation of small organic compounds to accelerate the drug discovery process.1 Solid-phase heterocyclic compounds have received special attention because of their high degree of structural diversity and biologically interesting properties. As a result, an increasing range and number of pharmaceuti cally useful heterocyclic compounds have been prepared recently using solid-phase methodology. Oxindoles are interesting synthetic targets because of their various biologi cal activities such as growth hormone secretagogues, CDKs inhibitors, anticancer compounds, and AChE and BChE inhibitors. There are many methods that have been devel oped for the synthesis of oxindoles both in solution phase and on solid phase, such as derivatization of other hetero cycles, cyclization of o-aminophenylacetic acid derivatives, reduction of isatins, Friedel-Crafts reaction (Stolle syn thesis)," radical cyclizations, intramolecular Heck reac tions, and Pummerer cyclizations. These methods are very useful for the construction of the oxindoles; however, Stolle syntheses are of limited scope because of the harshly acidic conditions required, while many of the other methods are limited by the types of oxindoles that may be prepared because of the specifically functionalized precursors required or because the starting materials are not available conve niently. The Gassman oxindole synthesis, which proceeds from a substituted aniline and ethyl (methylthio) acetate via chlorination of the sulfide and subsequent treatment with an arylamine and base such as triethylamine, is one of the most generally useful methods in terms of scope, starting material availability, brevity, and reproducibility.