Exploiting 3‐Methyleneisoindolinones as In Situ Generated Reactive Intermediates in the Synthesis of Tetrasubstituted Carbon Center

A straightforward method for constructing a tetrasubstituted carbon center through the in situ formation of 3-methyleneisoindolinones as reactive intermediates has been developed. This process involves an acid-catalyzed Meyer-Schuster rearrangement of isoindolinone-based propargylic alcohols, followed by an intermolecular Friedel-Crafts alkylation, which yields 3,3-disubstituted isoindolinones.

Abstract

In this study, we describe the operationally simple construction of a tetrasubstituted carbon center utilizing in situ formation of 3-methyleneisoindolinones as reactive intermediates. An acid-catalyzed Meyer–Schuster rearrangement of isoindolinone-based propargylic alcohols followed by an intermolecular Friedel–Crafts alkylation assembles the 3,3-disubstituted isoindolinones, an important architectural motif found in numerous biologically active compounds. Highly inert to structural changes in building blocks, this robust transformation allows the quick build-up of a library of compounds with an embedded isoindolinone core. In addition, the in situ formation of the activated intermediate allows a selective installation of various structural characteristics .

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