Palladium‐Catalyzed Cascade Reaction for the Synthesis of Substituted Isoindolines

Abstract

Isoindoline heterocycles have demonstrated potential in medicinal chemistry as they exhibit activity across diverse biological targets. They are present in molecules which act as bronchodilaters, N-methyl-d-aspartate agonists, multidrug resistance reversal agents, and fibrinogen receptor antagonists. While several approaches to the synthesis of unsubstituted or monosubstituted isoindolines have been reported, few methods exist to produce disubstituted isoindolines with high diastereoselectivity. In addition, there are no diastereoselective methods for the synthesis of 1,3-disubstituted isoindolines that allow for incorporation of readily available boronic acids, which are practical building blocks in medicinal chemistry. Synthetic methods for isoindoline synthesis that provide straightforward introduction of substitutents on the heterocycle would enable preparation of families of biologically significant compounds. We designed a cascade sequence for isoindoline synthesis that we anticipated could be catalyzed by a palladium(II) complex and would utilize boronic acids as a starting material (Scheme 1). The cascade reaction would initiate with arylation of imine 1. The resultant sulfonamide would engage the pendant allylic acetate by aminopalladation; b-acetoxy elimination would release the isoindoline product. A major challenge was identification of a catalyst with the appropriate electronic balance to facilitate all steps in the catalytic cycle. While nucleophilic arylation of imines requires electron-donating ligands, migratory insertion is generally promoted by palladium(II) catalysts with electrophilic character. We selected phosphinite palladacycle 3, which is a catalyst with demonstrated activity for arylation of imines, with the thought that the p-accepting phosphonite would balance s donation from the aryl group. In practice, we have found this complex to be an effective catalyst for our cascade sequence (see below). We began our investigation with reaction conditions similar to those employed for imine arylation. At room temperature, in the presence of catalyst 3, effective arylation of 1 with phenyl boronic acid occurs (Table 1, entry 1). Elevated reaction temperatures promote the cyclization reaction (Table 1, entry 2; Method A). Notably, isoindoline 2 is generated as a single diastereomer under these reaction conditions. Scheme 1. Proposed synthesis of isoindoline derivatives. L= ligand, Ts=4-toluenesulfonyl.