Background: The 3-substituted 3-hydroxyisoindolinone motif is common to a variety of compounds
with potent biological activities. In recent years, they have also been increasingly used as substrates in
various asymmetric transformations. Current methods for their preparation either do not tolerate wide range of
functional groups, or yield 3–hydroxyisoindolinones as N–substituted products, which makes them inapplicable
as substrates for the asymmetric transformations.
Objective: Aim of this study was a detailed examination of the synthesis of 3–substituted 3–
hydroxyisoindolinones comprising various functional groups and unsubstituted phthalimide nitrogen.
Method: Grignard and organolithium reagents were employed as nucleophiles for the synthesis of 3–
substituted 3–hydroxyisoindolinones under various reaction conditions.
Results: Phenyl substituents with electron donating groups are easily introduced by employing a Grignard reaction,
while electron–poor arenes require a lithium exchange or direct lithiation strategy. The protocols are
tolerant of various functional groups on the nucleophile, and a wide range of 3–hydroxyisoindolinones were
afforded in good to excellent yields.
Conclusion: Simple and inexpensive method for the synthesis of 3-substituted 3-hydroxyisoindolinone has
been developed. By tweaking the reaction conditions, described protocols are tolerant of a wide range of functional
groups, and yield 3–substituted isoindolinone alcohols with unsubstituted phthalimide nitrogen.